MIRPUR UNIVERSITY OF SCIENCE AND TECHNOLOGY

Session: 2022-26

Roll no. : FA22-BHN-012

FA22-BHN-013
Subject : Bio-chemistry (1104)

Submitted by : Azalfa , Emaan

Submitted to: Prof. Farhat Wajad

ASSIGNMENT: INVOLVEMENT OF CELL SIGNALING

IN CANCER

Article: Degradation of cell signaling in cancer (Filippo G. Giancotti )

Date : 10-12-2022
 SUMMARY
Cell undergo expansion that regulate their ability to perform cell cycle whereas in prevalent
oncogenic mutation disrupt the normal operation of them to deregulate mitogenesis resistance.
Receptors and cell signaling: The ability of normal cells to survive and grow depends on
growth factor receptors such as tyrosine kinase activity (RTKs)1. The ligand binding of RTKs
leads to phosphorylation of tyrosine present within the receptor tails or on surrogate proteins
(such as IRS) creating sites for signaling adaptors that have phosphotyrosine-bindings2 which
occur by inactivation of the GTPase-activating proteins p120 and neurof i bromin. As Ras
signaling activate Myc and Ets transcription factors 3 blocking the ability of GSK3-b to
phosphorylate and to mark it for ubiquitin-dependent degradation4. Whereas Raf activate the
MEK–ERK cascade, which is initially recruited to the plasma membrane by tyrosine-
phosphorylated receptors or surrogate adaptors, enables conversion of PIP2 to PIP3 which
attracts Akt, which upon activation inactivates multiple effectors . Through these mechanisms,
receptor tyrosine kinases promote cell survival, progression through the G1 phase of the cell
division cycle, and cell migration.
Retardation of cell signaling pathways: Oncogenic mutations causing deregulated activation of
receptor tyrosine kinases or their downstream signaling. The major effector pathways activated
by RTKs are depicted by proto-oncogenic proteins. It leads to reprogramming of metabolism that
changes energy from aerobic glycolysis5 to synthesis of amino acids, lipids, and nucleotides . In
order to produce these changes, Akt promotes the utilization of glucose by increasing
translocation of membrane transporters, such as Glut4 Deregulated Myc promotes mitochondrial
utilization that collabs with HIF1 which inactivates flow of pyruvate into the tricarboxylic acid
(TCA)6 cycle. The loss of p53 decreases glycolysis, which is required for the assembly of
cytochrome oxidase complex. Due to which metabolic reprogramming is increased and the
production of NAPDH which buffer the reactive oxygen species (ROS) produced by oncogenic
mitogenic signaling. Oncogenic mutations target several elements of this signaling network such
as TGF-b receptors, restrict progression through G1 by inhibiting the expression of Myc and by
elevating the levels of the Cdk inhibitors.
To overcome intrinsic form of tumor suppression, incipient neoplastic cells need to evade
apoptosis. To induce invasive growth, they must disrupt epithelial adhesion and polarity.

1 Lemmon, M.A. and Schlessinger, J. (2010) Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134.
2 Pawson, T. (2004) Specif i city in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell 116,
191–203.
3 Sears, R.C. and Nevins, J.R. (2002) Signaling networks that link cell proliferation and cell fate. J. Biol. Chem. 277, 11617–11620.
4 Sherr, C.J. (2004) Principles of tumor suppression. Cell 116, 235–246. F.G. Giancotti / FEBS Letters 588 (2014) 2558–2570 2569
5 Warburg, O. (1956) On respiratory impairment in cancer cells. Science 124, 269–270.

6 Gordan, J.D., Thompson, C.B. and Simon, M.C. (2007) HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation.

Cancer Cell 12, 108–113.