Question

Question 5: Signal Transduction

A. Cancer cells often have acquired mutations that disrupt their ability to undergo programmed cell death. Name three (3) mutations (loss of function or gain of function) in the RTK-PI3 kinase-AKT pathway that would lead to the survival pathway being “always on”. And of course, for each, explain your reasoning.

B. There is a phosphatase called PTEN that dephosphorylates phosphorylated inositol phospholipid (PIP₃). Would a loss of function in PTEN cause cells to undergo programmed cell death and or prevent programmed cell death from occurring? Explain your reasoning.

C. Imagine that the receptor in a Jak/Stat pathway is mutated such that it cannot be phosphorylated. Which steps in the Jak/Stat pathway will still happen and which will not? Be sure to describe each step of the pathway and whether or not it would be happening in this scenario.

Answer 1

A.

1.The importance of PI3Ks in cancer was confirmed by the discovery that the PIK3CA gene encoding p110α is frequently mutated in some of the most common human tumors .These genetic alterations of PIK3CA consist exclusively of somatic missense. Two of the most frequent PIK3 mutations, E545Kand H1047R, have been shown to enhance PI(3,4,5)P3 levels, activate AKT signaling, and induce cellular transformation .

Recent cancer genomic analysis of human glioblastomas (GBM) showed that the PIK3R1gene, encoding the p85α regulatory subunit, was mutated in up to 10% of tumors analyzed.

2.Amplification of AKT1/2 has been reported in various tumor types.Recently, an activating mutation in the PH domain of AKT1 (E17K) was identified in melanoma, breast, colorectal and ovarian cancers,which results in growth factor-independent membrane translocation of AKT and increased AKT phosphorylation levels.

3.Activation of the PI3K signaling pathway contributes to cell proliferation, survival and motility as well as angiogenesis, which are responsible for all important aspects of tumorigenesis. For this reason many pharmaceutical companies and academic laboratories are actively developing inhibitors targeting PI3K and other key components in the pathway.

B.The phospholipid PI(3,4,5)P3generated by activated class I PI3Ks is the second messenger that drives multiple downstream signaling cascades regulating cellular processes .The cellular level of PI(3,4,5)P3 is tightly regulated by the opposing activity of PTEN. PTEN, an important tumor suppressor, functionally antagonizes PI3K activity via its intrinsic lipid phosphatase activity that reduces the cellular pool of PIP3 by converting PI(3,4,5)P3 back to PI(4,5)P2 . Loss of PTEN will result in unrestrained signaling by the PI3K pathway a nd this leading to cancer .

C.If the receptor get mutated,then the transcription factor (STAT) can't be phosphorylated by JAK ,(a soluble Tyr kinase) and it can't enter the nucleus and can't express the genes.Ultimately the pathway can't activated without phosphorylation.