bHLH-containing domain into the cytosol.

This fragment, called nSREBP (nuclear SREBP), is rapidly translocated into the nucleus.
There it activates transcription of genes containing sterol regulatory elements (SREs) in their promoters, such as those encoding the
LDL receptor and HMG-CoA reductase. Thus a reduction in cellular cholesterol, by activating the insig-1(2)/SCAP/SREBP pathway,
triggers expression of genes encoding proteins that both import cholesterol into the cell (the LDL receptor) and synthesize
cholesterol from small precursor molecules (HMG-CoA reductase).
After cleavage of SREBP in the Golgi, SCAP apparently recycles back to the ER, where it can interact with insig-1(2) and
another intact SREBP molecule. High-level transcription of SRE-controlled genes requires the ongoing generation of new nSREBP
because it is degraded fairly rapidly by the ubiquitin-mediated proteasomal pathway (see Chapter 3). The rapid generation and
degradation of nSREBP help cells respond quickly to changes in levels of intracellular cholesterol.
Under some circumstances (e.g., during cell growth), cells need an increased supply of all the essential membrane lipids and
their fatty acid precursors (which requires coordinate regulation). To make steroid hormones, cells sometimes need greater amounts
of some lipids (such as cholesterol) than others, such as phospholipids (which requires differential regulation). How is such
differential production achieved? Mammals express three known isoforms of SREBP: SREBP-1a and SREBP-1c, which are
generated from alternatively spliced RNAs produced from the same gene, and SREBP-2, which is encoded by a different gene.
Together, these intramembrane cleavage–activated transcription factors control expression of proteins that regulate availability not
only of cholesterol, but also of fatty acids and the triglycerides and phospholipids made from fatty acids. In mammalian cells,
SREBP-1a and SREBP-1c exert a greater influence on fatty acid metabolism than on cholesterol metabolism, whereas the reverse is
the case for SREBP-2.

KEY CONCEPTS OF SECTION 16.7

Signaling Pathways Controlled by Protein Cleavage: Notch/Delta, SREBP, and A lzheimer’s

Disease
r Many important growth factors and other signaling proteins such as EGFs are synthesized as transmembrane proteins; regulated
cleavage of the precursor near the plasma membrane by members of the matrix metalloprotease
(MMP) family releases the active molecule into the extracellular space to signal distant cells.
r On binding to its ligand, Delta, on the surface of an adjacent cell, the receptor Notch protein undergoes two proteolytic cleavages
(see Figure 16-36). The released Notch cytosolic segment then translocates into the nucleus and modulates transcription of target
genes critical in determining cell fate during development.
r Cleavage of membrane-bound precursors of members of the EGF family of signaling molecules is catalyzed by ADAM
metalloproteases. Inappropriate cleavage of these precursors can result in abnormal cell proliferation, potentially leading to
cancer, cardiac hypertrophy, and other diseases.
r γ-Secretase, which catalyzes the regulated intramembrane proteolysis of Notch, also participates in the cleavage of amyloid
precursor protein (APP) into a peptide that forms plaques characteristic of Alzheimer’s disease (see Figure 16-37).
r In the insig-1(2)/SCAP/SREBP pathway, the active nSREBP transcription factor is released from the Golgi membrane by
intramembrane proteolysis when cellular cholesterol is low (see Figure 16-38). It then stimulates the expression of genes
encoding proteins that function in cholesterol biosynthesis (e.g., HMG-CoA reductase) and cellular import of cholesterol (e.g.,
LDL receptor). When cholesterol is high, SREBP is retained in the ER membrane complexed with insig-1(2) and SCAP (see
Figure 16-38).

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action

In the introduction to Chapter 15, we noted that the same hormone often acts on several types of body cells to coordinate specific
physiological responses. And each cell in the body has multiple types of hormone receptors on its surface and in its cytosol;
different hormones binding to these receptors can induce similar or dissimilar cellular responses. In this section, we consider how
multiple hormones and signal transduction pathways interact, focusing on one of the most important physiological control
systems: regulation of the body’s needs for the metabolites glucose and fatty acids. Defects in these pathways lead to major
diseases, including diabetes and cardiovascular disease; obesity itself can lead to these and other diseases, with dire consequences
for the individual and increasingly for public health.
 Cellular responses to changes in other nutrients, which are largely reflected in alterations in gene expression, are covered in
Chapter 9.

Insulin and Glucagon Work Together to Maintain a Stable Blood Glucose Level
During normal daily living, the maintenance of normal blood glucose concentrations depends on the balance between two peptide
hormones, insulin and glucagon, which are made in distinct pancreatic islet cells and elicit different cellular responses. Insulin,
which lowers blood glucose, contains two polypeptide chains linked by disulfide bonds and is synthesized by the β cells in the
islets (see
Figures 14-23 and 14-24). Glucagon, a monomeric peptide, is produced by the α islet cells and raises blood glucose. The
availability of blood glucose is regulated during periods of abundance (following a meal) or scarcity (following fasting) by the
adjustment of insulin and glucagon concentrations in the blood.
Our focus here will be on the key hormone insulin, which acts in several ways to reduce the level of blood glucose:
r Within seconds, insulin induces an increase in the uptake of glucose from the blood into muscle and fat cells, primarily by
increasing the number of GLUT4 glucose transporters on the plasma membrane (see Figure 16-40 below).
r Within seconds to minutes, insulin stimulates glycogen synthesis from glucose in the liver.
r Over a longer time frame, insulin acts on the liver to inhibit synthesis of enzymes that catalyze the synthesis of glucose from
smaller metabolites, a process termed gluconeogenesis.
r Insulin enhances the formation of adipocytes from progenitor cells, increasing the body’s storage of fatty acids as triglycerides.
r Insulin acts on the nearby α cells in the pancreatic islets to inhibit glucagon synthesis.
A lowering of blood glucose stimulates glucagon release from pancreatic α cells. Like the epinephrine receptor, the glucagon
receptor, found primarily on liver cells, is coupled to the G αs protein, whose effector protein is adenylyl cyclase. The binding of
glucagon to this receptor induces a rise in cAMP, leading to activation of protein kinase A, which inhibits glycogen synthesis and
promotes glycogenolysis, yielding glucose 1-phosphate (see Figures 15-28a and 15-35b). Liver cells convert glucose 1-phosphate
into glucose, which is released into the blood, thus raising blood glucose back toward its normal fasting level.

A Rise in Blood Glucose Triggers Insulin Secretion from the 𝛃 Islet Cells
After a meal, when blood glucose rises above its normal level of 5 mM, the pancreatic β cells respond to the rise in glucose (and
the concurrent rise in amino acids) by releasing insulin into the blood (Figure 16-39). We saw in Chapter 14 that these cells store
insulin in a dehydrated, almost crystalline form in secretory vesicles; as with all regulated secretory pathways, secretion is
triggered by a rise in cytosolic Ca2+. Insulin secretion is triggered by a rise in extracellular glucose, which causes a proportionate
increase in the rate of glucose entry into the cells and a corresponding increase in the rate of glycolysis. The resulting rise in the
concentration of cytosolic ATP causes closing of an ion channel unique to the β cells—an ATP-gated K+ channel—reducing the
efflux of K+ ions from the cell. The resulting depolarization of the plasma membrane triggers the opening of voltage-sensitive
Glucose Insulin-containing
GLUT2 secretory vesicle
1

Glucose
ADP
2 6
ATP
β pancreatic
Pyruvate
islet cell

~70 mV ~40 mV +
Ca 2
3 ATP 5
− − − − −− − − − − −− − − − − −−
+ + + + ++ + + + + ++ + + + + ++

4
K+ Voltage-sensitive
Ca2+ channels
ATP-sensitive
K+ channels

FIGURE 1639 Secretion of insulin in response to a rise in blood glucose. The entry of glucose into pancreatic β cells is mediated by the GLUT2
glucose transporter (step 1 ). Because the Km for glucose of GLUT2 is 20 mM, a rise in extracellular glucose from 5 mM, characteristic of the fasting
state, causes a proportional increase in the rate of glucose entry (see Figure 11-4). The conversion of glucose into pyruvate is thus accelerated,
resulting in an increase in the concentration of ATP in the cytosol (step 2 ). The binding of ATP to ATP-sensitive K + channels in the β cells closes those
channels (step 3 ), thus reducing the efflux of K+ ions from the cell. The resulting small depolarization of the plasma membrane (step 4 ) triggers the

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action 3

opening of voltage- sensitive Ca2+ channels (step 5 ). The influx of Ca2+ ions raises the cytosolic Ca2+ concentration, triggering the fusion of insulin-
containing secretory vesicles with the plasma membrane and the secretion of insulin (step 6 ). See J. Q. Henquin, 2000, Diabetes 49:1751.

Ca2+ channels, an increase in cytosolic Ca2+, and insulin secretion.

In Fat and Muscle Cells, Insulin Triggers Fusion of Intracellular Vesicles Containing the GLUT4 Glucose
Transporter to the Plasma Membrane
The released insulin circulates in the blood and binds to insulin receptors, which are present on many different kinds of cells,
including muscle and adipocyte cells. The insulin receptor, a receptor tyrosine kinase, activates several signal transduction
pathways, including the one leading to the activation of protein kinase B (PKB; see Figure 16-29). In this case, the main action of
the PKB signaling pathway—an increase in uptake of glucose from the blood—is manifest within minutes. Since glucose uptake
is the rate-limiting step in glucose utilization, this action results in rapid lowering of the blood glucose level.
Like those of most body cells, the plasma membranes of fat and muscle cells contain the GLUT1 glucose transporter, which
allows the cell to import sufficient glucose

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action 4

 (a) Tổng cộng (b ) Insulin
GLUT4 Glucose

Glut4 10
Đường Exocyst
Kiểm soát N
Thụ thể
insulin

9 7
Fusion của
RALA Glut4 vesicles
N GTP
P1 3 ’ kinase Với huyết tương Endocytosis 11
Insulin
membrane
điều trị
N 3 RALA
GAP 6b
P

PKB 8

P 5
Rab
4 GAP GTP

AS 160 Rab 8,
10, 14
Kinesin

HÌNH THỬ NGHIỆM

16 
40 Insulin kích thích các tế 6a
Bào chất báo gây ra translocation Vi ống
của GLUT4 từ các túi nội bào
đến mem huyết tương
brane. Nuôi cấy các tế
bào mỡ được thiết kế để biểu thị 1
Mảnh kéo
chimeric protein bao gồm
GLUT4 với một protein màu xanh lá
cây fluores-cent(GFP) kết hợp với
C-terminus là một kính hiển vi 2
quỳnh quang tiêu
Endosome
Trong trường hợp không có
insulin, hầu như tất cả các
GLUT4 là trong mem-branes nội 12
bào. Điều trị insulin kích hoạt
hạch của các màng GLUT4- P
có chứa với màng Protease Kéo
Plasma . Mũi tên nổi 1
bật GLUT4 hiện diện ở
Màng plasma; N indicates
cho biết vị trí của hạt nhân (b)
b) Trong tế bào chất béo và cơ bắp
Insulin hành vi trong nhiều bước để tăng mức độ GLUT4 ở các màng plasma một monomeric GTP-binding protein, RALA. PKB kích thích sự kiện
Trong tế bào nghỉ ngơi phần lớn các protein là GLUT4 được bản địa hóa cho này màn kết hợp p hosphorylating và do đó bất hoạt hóa của
các túi lưu trữ chuyên biệt GLUT4 (GSVs), được gắn vào các proteins ma trận RALA GAP protein RGC ( bước 8 ), cho phép RALA trong trạng thái
trận Glogi bới các protein TUG. Ràng buộc của insulin để các thụ thể hoạt động GTP-bound ( bước 9 ). Sự tăng kết quả trong màng plasma
Insulin dẫn đến kích hoạt một protease ( bước 1 mà tách các protein GLUT4 cho phép các tế bào kết hợp glucose từ các chất lỏng ngoại bào
TUG phát hành GLUT4 có chứa các túi , ( bước 2 ), sau đó di chuyển với tác dụng khoảng 10 lần của các tế bào không kích thích
theo các vi ống được trang bị động cơ kinesin (xem Chương 18), với bề dọc (bươs10 ). Sau khi loại bỏ insulin, màng plasma GLUT4 được
mặt tế bào . Insulin cũng kích hoạt PKB ( Bước 3 ; xem Hình 16-29). PKB sau internalized bởi endocytosis (bước 11) và cuối cùng vận chuyển đến GSVs
đó phosphorylates Rab GAP protein AS160 ( Bước 4 ), Có khả năng ( bước 12 ).Nhiều proteins khác , không được hiển thị ở đây tham khảo các
đẩy nhanh quá trình thủy phân GTP Rab8, Rab10, và Rab14. Các protein Rab tín hiệu và túi vừa chóm nở ở các sự kiện fusion .Xem J. Bogan,
này tích lũy trong trạng thái hoạt động của GTP-bound ( bước 5 ) và 2012, Annu. Rev. Biochem.81:507, D. Leto và A. Saltiel, 2012, Nat. Rev.
Cho phép các túi lưu trữ GLUT4 di chuyển dọc theo các ống đến bề mặt Mol. Cell Biol.13 :383, and J. Belman et al., 2014, Rev. Endocr. Metab.
Mặt tế bào (Bước 6a và 6b ). Cuối cùng, các GSVs cầu chì với màng Disord. 15 :55. [Part (a) C. Yu et al., 2007,
J. Biol. Chem282:7710; ©2007 American
plasma ( Bước 7 ). Bước này được xúc tác bởi các exosyst và cũng bởi Society for Biochemistry và Molecular Biology.]

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action 5

 for its basal metabolic needs. Fat and muscle cells also express large amounts of the insulin-responsive glucose transporter
GLUT4; in resting (unstimulated) cells, virtually all of the GLUT4 is localized to small vesicles in the cytosol ( Figure 16-40).
While some GLUT4 is in endosomes, most is in a unique small organelle termed the GLUT4 storage vesicle (GSV). In these
vesicles, much of the GLUT4 is tethered to the Golgi matrix, a network of coiled-coil proteins surrounding the Golgi complex, by
a protein termed TUG.
In addition to activating the PI-3 kinase/PKB pathway, the insulin receptor phosphorylates several other target proteins.
Together, these signals cause the movement of GLUT4-containing vesicles to the plasma membrane and then the fusion of these
vesicles with the plasma membrane. The resulting immediate tenfold increase in the number of GLUT4 molecules on the cell
surface increases glucose influx proportionally, thus lowering blood glucose (Figure 16-40b):
r Insulin triggers, by a signaling pathway that is only now being completely identified, activation of a protease that catalyzes a
site-specific endoproteolytic cleavage of TUG, separating the N-terminal GLUT4-binding segment from the rest of the protein
that is anchored to the Golgi matrix. This cleavage allows the GLUT4 vesicles to move to the plasma membrane.
r Recall that certain monomeric GTP-binding proteins are essential for the budding of intracellular transport vesicles (e.g., Sar
proteins; see Figures 14-6 and 14-8); others, the Rabs, are essential for vesicle fusion (see Figure 14-10). PKB phosphorylates,
and by so doing inactivates, two GAP proteins termed AS160 and RGC. In the basal unstimulated state, these GAPs inhibit Rab
function by enhancing their rates of GTP hydrolysis, thus keeping the GLUT4 storage vesicles from moving to and fusing with
the plasma membrane. Inhibition of these GAPs allows these monomeric GTP-binding proteins in fat and muscle cells to
accumulate in their active GTP-bound state. These proteins catalyze multiple steps in the GLUT4 pathway, including transport of
the GLUT4 storage vesicles along microtubules to the cell surface and, together with the exocyst (see Chapter 14), fusion of
these vesicles with the plasma membrane (see Figure 16-40b).
As the blood glucose level drops, insulin secretion and insulin blood levels drop, and insulin receptors are no longer activated
as strongly. In fat and muscle cells, plasmamembrane GLUT4 becomes internalized by endocytosis and stored in intracellular
membranes, lowering the level of cellsurface GLUT4 and thus of glucose import.

Insulin Inhibits Glucose Synthesis and Enhances Storage of Glucose as Glycogen

Within minutes, insulin stimulation of muscle cells enhances the conversion of glucose to glycogen, and PKB, activated
downstream of the insulin receptor, plays a crucial role in this process as well. Active PKB phosphorylates GSK3 (the same
enzyme that functions in the Wnt and Hh pathways). In resting (non-insulin-stimulated) cells, GSK3 phosphorylates glycogen
synthase and thus inhibits its activity. In contrast, in insulin-treated muscle, GSK3 is phosphorylated by PKB and cannot
phosphorylate glycogen synthase; thus insulin-stimulated activation of PKB results in net short-term activation of glycogen
synthase and glycogen synthesis.
Insulin also acts on hepatocytes (liver cells) to inhibit glucose synthesis from smaller molecules (gluconeogenesis), such as
lactate, pyruvate, and acetate (see Chapter 12) and to enhance glycogen synthesis from glucose. Many of these effects are manifest
at the level of gene transcription because insulin signaling reduces the expression of genes whose encoded enzymes simulate
synthesis of glucose from small metabolites. The net effect of all these actions is to lower blood glucose to the fasting concentration
of about 5 mM while storing the excess glucose intracellularly as glycogen for future use.
If the blood glucose level falls below about 5 mM—for example, due to sudden muscular activity—reduced insulin secretion
from pancreatic β cells induces pancreatic α cells to increase their secretion of glucagon into the blood and quickly trigger an
increase in blood glucose levels.

Unfortunately, these intricate and powerful control systems sometimes fail, causing serious, even life-
threatening, disease, mainly diabetes mellitus. In diabetes, the regulation of blood glucose is impaired, leading to persistent
elevated blood glucose concentrations (hyperglycemia) that, if left untreated, lead to major complications, including blindness,
kidney failure, and limb amputations. Type 1 diabetes mellitus, common in children and young adults, is caused by an autoimmune
process that destroys the insulinproducing β cells in the pancreas. Sometimes called insulindependent diabetes, this form of the
disease is generally responsive to regulated lifelong insulin injections and constant monitoring of blood glucose levels.
Most adults in developed countries with diabetes mellitus have type 2, sometimes called non-insulin-independent diabetes; this
condition results from a decrease in the ability of muscle, fat, and liver cells to respond to insulin and from a loss of insulin-
producing cells as the body tries to compensate for an elevated glucose level by overproducing insulin. While the underlying causes
of this form of the disease are not well understood, obesity is correlated with a huge increase in the incidence of diabetes. As we see
in the next section, obesity also contributes to the malfunction of adipocytes, the cells that store fatty acids as triglycerides. The
resulting accumulation of lipids (particularly diacylglycerols and sphingolipids) in muscle and liver impairs insulin action in these

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action 6

tissues. Further identification of the signaling pathways that control energy metabolism is expected to provide insight into the
pathophysiology of diabetes, hopefully leading to new methods for its prevention and treatment. ■
Multiple Signal Transduction Pathways Interact to Regulate Adipocyte Differentiation Through PPAR𝛄, the
Master Transcriptional Regulator
Insulin is also a major inducer of the formation of white adipocytes, commonly called “fat cells.” Adipocytes are the body’s major
fat storage depots; mature adipocytes contain a few triglyceride droplets that occupy the bulk of the cell. Adipocytes are also
endocrine cells and secrete several signaling proteins that affect the metabolic functions of muscle, liver, and other organs.
Adipocytes are the one type of cell in the body that can increase in number almost without limit. Readers in every country do not
need to be reminded that obesity is a growing public health problem, and that it is a major risk factor not only for diabetes but also
for cardiovascular diseases, such as heart attacks and stroke, and for certain cancers.
As we discuss in Chapter 21, several types of stem cells in vertebrates are used to generate specific types of differentiated cells.
The mesenchymal stem cell, which resides in the bone marrow and other organs, gives rise to progenitor cells that in turn can form
either adipocytes, cartilageproducing cells, or bone-forming osteoblasts. The adipocyte progenitor, called the preadipocyte, has lost
the potential to differentiate into other cell types. When treated with insulin and other hormones, preadipocytes undergo terminal
differentiation; they acquire the proteins that are necessary for lipid transport and synthesis, insulin responsiveness, and the
secretion of adipocyte-specific proteins. Several lines of cultured preadipocytes can differentiate into adipocytes and express
adipocyte-specific mRNAs and proteins, such as enzymes required for triglyceride synthesis.
The transcription factor PPARγ, a member of the nuclear hormone receptor family, is the master transcriptional regulator of
adipocyte differentiation. As evidence, recombinant expression of PPARγ in many fibroblast lines has been found sufficient to
trigger the differentiation of these cells into adipocytes. Conversely, knocking down the gene for PPARγ in preadipocytes prevents
their differentiation into adipocytes. Most hormones, such as insulin, that promote adipogenesis do so at least in part by activating
expression of PPARγ. PPARγ, in turn, binds to the promoters of most adipocyte-specific genes, including genes encoding proteins
needed in the insulin-signaling pathway, such as the insulin receptor and GLUT4, and induces their expression. Like other members
of the nuclear hormone receptor family, such as steroid hormone receptors (see Chapter 9), which become activated when they bind
their ligand, PPARγ is also thought to bind a ligand, possibly an oxidized derivative of a fatty acid.
Another transcription factor, C/EBPα, is induced during adipocyte differentiation and also directly induces many adipocyte
genes. Importantly, C/EBPα induces expression of the PPARγ gene, and PPARγ induces expression of C/EBPα, leading to a rapid
increase in both proteins during the first two days of differentiation. Together, PPARγ and C/EBPα induce expression of all genes
required for the differentiation of preadipocytes into mature fat cells.
Many signaling proteins, such as Wnt and TGF-β, oppose the action of insulin and prevent preadipocyte differentiation into
adipocytes. As Figure 16-41 shows, transcription factors activated by receptors for these hormones prevent expression of the
PPARγ gene, in part by blocking the ability of C/EBPα to induce PPARγ gene expression. Thus multiple extracellular signals act
in concert to regulate adipogenesis, and the signal transduction pathways activated by them intersect at the regulation of
expression of one key “master” gene, encoding PPARγ.

Inflammatory Hormones Cause Derangement of Adipose Cell Function in Obesity

The problem with obesity is not just the weight of the added adipose cells; the metabolism of these cells becomes abnormal, and
insulin signaling is reduced. In many individuals, this leads to development of type 2 diabetes. Much of the problem comes from
macrophages and other immune-system cells that invade and populate obese adipose tissue, probably attracted by the necrotic
adipose cells that accumulate and the greasy lipid droplets they release. These macrophages secrete several so-called
inflammatory hormones that profoundly affect the metabolism of the nearby adipose cells. Two of these hormones, TNFα and IL-
1, bind to their respective receptors on adipose cells and induce activation of the transcription factor NF-κB (see Figure 16-35a).
NF-κB, in turn, induces the expression of several proteins that interfere with insulin signaling, including SOCS proteins; as with
cytokine receptors (see Figure 16-14b), SOCS proteins bind to phosphorylated tyrosines in the insulin receptor cytosolic domain,
inhibit kinase activity, and lead to degradation of the insulin receptor and associated signaling proteins.
Additionally, NF-κB represses the expression of several essential components of the insulin-signaling pathway, including
GLUT4 and PKB. NF-κB also induces the expression of inflammatory cytokines such as TNFα, which in turn act in an autocrine
or paracrine manner on adipocytes and exacerbate the development of insulin resistance. Among the biochemical alterations in
adipocyte metabolism induced by these “inflammatory” hormones is the hydrolysis of triglycerides into free fatty acids and
glycerol; excess fatty acids are released into the blood, whence they can accumulate in and induce insulin resistance in liver and
muscle. This in turn leads to an increase in blood glucose, and to overproduction of insulin by the β islet cells in an attempt to
overcome the increasing insulin insensitivity in fat, muscle, and liver cells—all leading to what has become a major public health
problem in all developed countries in the twenty-first century, the type 2 diabetes epidemic.

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action 7

 (a) Thúc đẩy cảm ứng (b) Ức chế cảm ứng (c) Ức chế cảm ứng
Genes mỡ Genes mỡ Genes mỡ
Insulin Wnt TGF- β

Wnt Frizzled (Fz)

IGF1 TGF- β
receptor IGF1 và receptor
P
insulin
receptors Smad3 Smad3

P13’ kinase β -Catenin

PKB TCF

Necdin GATA2

Regulatory C/EBP α
sequences
C/EBP α
Cảm ứng các
genes mỡ
Regulatory PPAR γ
sequences
PPAR γ

HÌNH 16-41 Nhiều con đường truyền tính hiệu tương tác để
điều chỉnh adipocyte sự khác biệt . Các yếu tố phiên âm PPAR γ
( tím ) là điều chỉnh chính chủ của sự khác biệt adipocyte cùng
với C/EBP α, nó gây ra biểu hiện của tất cả các gen cần thiết differentia-
tion của preadipocytes vào tế bào chất béo.Cả 2 PPAR γ và C/EBP α là
gây ra sớm trong adipogenesis; mỗi người trong số họ tăng cường
transcrip-tion của gen mã hóa khác( một mũi tên ở phần cuối của 1 dòng
có nghĩa là tăng cường biểu hiện của các gen mục tiêu), dẫn đến sự gia
tăng nhanh chóng trong biểu hiện của cả 2 proteins trong 2 tháng đầu
tiên của sự khác biệt. Tín hiệu từ kích thích tố như insulin và từ các yếu tố
tăng trưởng như Wnt và TGF- β đó kích hoạt hoặc repress adipogenesis
được tích hợp trong hạt nhân bởi các yếu tố phiên mã điều chỉnh trực tiếp
hoặc gián tiếp— biểu hiện của các gen PPAR γ và C/EBP α .
(mỗi hình dạng T ở cuối cùng một dòng chữ cho thấy sự ức chế biểu hiện
của gen mục tiêu) (a) Insulin kích hoạt adipogenesis bởi một số con đường
dẫn đến kích hoạt biểu hiện PPAR γ, hai ftrong số đó được miêu tả ở
đây . Kích hoạt của protein kinase B (PKB) hạ lưu của IGF-1 và insulin
thụ thể tyrosine kinases dẫn đến đàn áp biêu hiện Necdin
expression; Necdin, bằng cách đều chỉnh các yếu tố phiên mã khác
nếu không sẽ repress biểu hiện của PPAR γ PKB cũng phosphory-lates
và cũng do đó bất hoạt các yếu tố phiên mã GATA2, mà khi
nonphosphorylated liên kết với các protein C/EBP α và ngăn chặn nó
kích hoạt biểu hiện của gen PPAR γ . Bằng ức chế hai repressors của insulin
gen PPAR γ ,do đó kích thích biểu hiện PPAR γ (b) Wnt và TGF- β
ức chế adipogenesis bằng cách giảm biểu hiện của gen PPAR γ
.Wnt tín hiệu gây ra sự phát hành của β -Catenin từ một sự phức hợp tế
bào chất và miễn phí- β-catenin liên kiết với các yêu tố phiên mã TCF (xem
hình 16-30) . Hoạt động TCF khối biểu hiện của các gen PPAR γ
và C/EBP αcó thể là ràn buộc với các chuỗi qui định họ. (c) Smad3,
kích hoạt bởi phosphoryl hóa sau TGF- β ràn buộc với các loại
I và II TGF- β thụ thể, liên kết với các protein C/EBP α và ngăn chặn
nó từ các biểu hiện kích hoạt của gen PPAR . γ Xem E. Rosen và
O. MacDougald, 2006, Nat. Rev. Mol. Cell Biol.7:885.

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action 8

KEY CONCEPTS OF SECTION 16.8

Integration of Cellular Responses to M ultiple Signaling Pathways: Insulin A ction

r A rise in blood glucose stimulates the release of insulin from pancreatic β cells (see Figure 16-39).
r Subsequent binding of insulin to its receptor on muscle cells and adipocytes leads to the activation of protein kinase B, which
activates several signal transduction pathways. Together with PKB-independent pathways, these pathways lead to translocation
of the GLUT4 glucose transporter from intracellular vesicles to the plasma membrane and thus to an increase in glucose uptake
and (in muscle) glycogen synthesis, resulting in a decrease in blood glucose (see Figure 16-40).
r A lowering of blood glucose stimulates glucagon release from pancreatic α cells. Binding of glucagon to its G p rotein– coupled
receptor on liver cells promotes glycogenolysis by the cAMP-triggered kinase cascade (similar to epinephrine stimulation under
stress conditions) and an increase in blood glucose (see Figures 15-28a and 15-35b).
r PPARγ, a member of the nuclear receptor f amily, is the master transcriptional regulator of adipocyte differentiation.
r Extracellular hormones such as insulin that promote adipocyte differentiation induce signal transduction pathways that lead to
enhanced production of PPARγ. Conversely, signaling proteins such as Wnt and TGF-β that prevent preadipocyte differentiation
activate signaling pathways that prevent expression of the PPARγ gene (see Figure 16-41).

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Key Terms
activation loop 730 phosphoinositides 748

adapter protein 741 PI-3 kinase pathway 749

constitutive 723 PPARγ 770

cytokines 727 presenilin 1 762

diabetes mellitus 769 primary cilium 757

erythropoietin (Epo) 727 protein kinase B (PKB) 750

Hedgehog (Hh) 755 PTEN phosphatase 751

HER family 735 Ras protein 739

insig-1(2)/SCAP/SREBP receptor tyrosine kinases

pathway 766 (RTKs) 726

insulin 766 regulated intramembrane

JAK/STAT pathway 727 proteolysis 764

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action 9

kinase cascade 739 scaffold proteins 748

MAP kinase 739 SH2 domains 730

matrix metalloprotease Smads 722

(MMP) family 761 SRE-binding proteins

NF-κB pathway 752 (SREBPs) 764

Notch/Delta pathway 761 transforming growth factor

nuclear-localization signal β (TGF-β) 722

(NLS) 724 Wnt 751

Review the Concepts

1. Name three features common to the activation of cytokine receptors and receptor tyrosine kinases. Name one difference
with respect to the enzyme activity of these receptors.
2. Erythropoietin (Epo) is a hormone that is produced naturally in the body in response to low O 2 levels in the blood. The
intracellular events that occur in response to Epo binding to its cell-surface receptor are well characterized. What molecule
translocates from the cytosol to the nucleus after (a) JAK2 activates STAT5 and (b) GRB2 binds to the Epo receptor? Why did
some endurance athletes use Epo to improve their performance (“blood doping”) until it was banned by most sports?
3. Explain how expression of a dominant-negative mutant of JAK blocks the erythropoietin (Epo)-cytokine signaling
pathway.
4. Even though GRB2 lacks intrinsic enzyme activity, it is an essential component of the epidermal growth factor (EGF)
signaling pathway that activates MAP kinase. What is the function of GRB2? What roles do the SH2 and SH3 domains play in
the function of GRB2? Many other signaling proteins possess SH2 domains. What determines the specificity of SH2
interactions with other molecules?
5. Once an activated signaling pathway has elicited the proper changes in target-gene expression, the pathway must be
inactivated. Otherwise, pathological consequences may

16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action 10

 result, as exemplified by persistent growth factor–initiated signaling in many cancers. Many signaling pathways possess intrinsic
negative feedback by which a downstream event in a pathway turns off an upstream event. Describe the negative feedback that
down-regulates signals induced by (a) erythropoietin and (b) TGF-β.
A mutation in the Ras protein renders Ras constitutively active (Ras D). What is constitutive activation? How does constitutively
active Ras promote cancer? What type of mutation might render the following proteins constitutively active: (a) Smad3, (b) MAP
kinase, and (c) NF-κB?
The enzyme Ste11 participates in several distinct MAP kinase signaling pathways in the budding yeast S. cerevisiae. What is the
substrate for Ste11 in the mating factor signaling pathway? When a yeast cell is stimulated by mating factor, what prevents the
induction of osmolytes required for survival in high-osmotic-strength media, given that Ste11 also participates in the MAP kinase
pathway initiated by high osmolarity?
Describe the events required for full activation of protein kinase B. Name two effects of insulin mediated by PKB in muscle cells.
Describe the function of the PTEN phosphatase in the PI-3 kinase signaling pathway. Why does a loss-of-function mutation in
PTEN promote cancer? Predict the effect of constitutively active PTEN on cell growth and survival.
Binding of TGF-β to its receptors can elicit a variety of responses in different cell types. For example, TGF-β induces
plasminogen activator inhibitor 1 in epithelial cells and specific immunoglobulins in B cells. In both cell types, Smad3 is
activated. Given the conservation of the signaling pathway, what accounts for the diversity of the response to TGF- β in various
cell types?
How is the signal generated by binding of TGF-β to cellsurface receptors transmitted to the nucleus, where changes in target-gene
expression occur? What activity in the nucleus ensures that the concentration of active Smads closely reflects the level of activated
TGF-β receptors on the cell surface?
The extracellular signaling protein Hedgehog can remain anchored to cell membranes. What modifications to Hedgehog enable it
to be membrane bound? Why is this property useful?
Explain why loss-of-function hedgehog and smoothened mutations yield the same phenotype in flies, but a loss-offunction
patched mutation yields the opposite phenotype.
Most mammalian cells have a single immobile cilium called the primary cilium, in which intraflagellar transport (IFT) motor
proteins (discussed in greater detail in Chapter 18) move elements of the Hedgehog (Hh) signaling pathway along microtubules.
What parts of the Hh signaling pathway would mutations in the IFT motor proteins Kif3A, Kif7, and dynein disrupt?
Why is the signaling pathway that activates NF-κB considered to be relatively irreversible compared with cytokine or RTK
signaling pathways? Nonetheless, NF-κB signaling must be down-regulated eventually. How is the NF-κB signaling pathway
turned off?
Describe two roles for polyubiquitinylation in the NF-κB signaling pathway.
What feature of Delta ensures that only neighboring cells are signaled?
What biochemical reaction is catalyzed by γ-secretase? Why was it proposed that a chemical inhibitor of this activity might be a
useful drug for treating Alzheimer’s disease? What possible side effects of such a drug would complicate this use?

References
Receptor Serine Kinases That Activate Smads
Deheuninck, J., and K. Luo. 2009. Ski and SnoN, potent negative regulators of TGF-β signalling. Cell Res. 19:47–57.
Massagué, J. 2012. TGFβ signalling in context. Nat. Rev. Mol.
Cell Biol. 13:617–630.
Xu, P., J. Liu, and R. Derynck. 2012. Post-translational regulation of TGF-β receptor and Smad signaling. FEBS Lett. 586:1871– 1884.
Cytokine Receptors and the JAK/STAT Signaling Pathway
Hattangadi, S., et al. 2011. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs and chromatin
modifications. Blood 118:6258–6268.
Pfeifer, A. C., J. Timmer, and U. Klingmuller. 2008. Systems biology of JAK/STAT signalling. Essays Biochem. 45:109–120.
Schindler, C., D. E. Levy, and T. Decker. 2007. JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 282:20059– 20063.
Receptor Tyrosine Kinases
Lemmon, M. A., and J. Schlessinger. 2010. Cell signaling by receptor tyrosine kinases. Cell 141:1117–1134.
Lemmon, M., J. Schlessinger, and K. Fergusun, eds. 2014. The EGFR family: not so prototypical receptor tyrosine kinases. Cold Spring Harb. Perspect.
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Tomas, A., C. Futter, and E. Eden. 2014. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol. 24:26–34.
The Ras/MAP Kinase Pathway
Chen, R., and J. Thorner. 2007. Function and regulation in MAPK signaling pathways: lessons learned from the yeast Saccharomyces cerevisiae.
Biochim. Biophys. Acta 1773:1311–1340.
Gastel, M. 2006. MAPKAP kinases—MKs—two’s company, three’s a crowd. Nat. Rev. Mol. Cell Biol. 7:211–224.
Matallanas, D., et al. 2011. Raf family kinases: old dogs have learned new tricks. Genes Cancer 3:232–260.

References
Phosphoinositide Signaling Pathways
Fayard, E., et al. 2010. Protein kinase B PKB/Akt, a key mediator of the PI3K signaling pathway. Curr. Top. Microbiol. 346:31–56.
Michell, R. H., et al. 2006. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem. Sci. 31:52–63.
Vogt, P. K., et al. 2010. Phosphatidylinositol 3-kinase: the oncoprotein. Curr. Top. Microbiol. Immunol. 347:79–104.

Signaling Pathways Controlled by Ubiquitinylation and Protein

Degradation: Wnt, Hedgehog, and NF-κB
Briscoe, J., and P. Thérond. 2013. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat.
Rev. Mol. Cell Biol. 14:416–429.
Goetz, S., and K. Anderson. 2010. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet.
11:331–344.
Iwai, K., et al. 2014. Linear ubiquitin chains: NF-κB signalling, cell death and beyond. Nat. Rev. Mol. Cell Biol. 15:503–508.
Nehers, C. 2012. The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13:767–779.
Wan, F., and M. Lenardo. 2010. The nuclear signaling of NFκB: current knowledge, new insights, and future perspectives. Cell Res. 20:24–33.
Signaling Pathways Controlled by Protein Cleavage: Notch/Delta,
SREBP, and Alzheimer’s Disease
Anderson, P., et al. 2012. Non-canonical Notch signaling:
emerging role and mechanism. Trends Cell Biol. 22:257–265.
Brown, M. S., and J. L. Goldstein. 2009. Cholesterol feedback: from S0choenheimer’s bottle to Scap’s MELADL. J. Lipid Res.
50:S15–S27.
Musse, A., et al. 2012. Notch ligand endocytosis: mechanistic basis of signaling activity. Semin. Cell Dev. Biol. 23:429–436.
Integration of Cellular Responses to Multiple Signaling Pathways:
Insulin Action
Bogan, J. 2012. Regulation of glucose transporter translocation in health and diabetes. Annu. Rev. Biochem. 81:507–532.
Leto, D., and A. Saltiel. 2012. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat. Rev. Mol. Cell Biol.
1:383–396.
Rosen, E., and O. MacDougald. 2006. Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7:885–896.

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