Chapter 20, Problem 21P

A generic signaling cascade is shown in the following figure. A growth factor (GF) binds to a growth factor receptor, activating the kinase function of an intracellular domain of the growth factor receptor. One substrate of the growth factor receptor kinase is another kinase, kinase A, that has enzymatic activity only when it is itself phosphorylated by the GF receptor kinase. Activated kinase A adds phosphate to a transcription factor. When it is unphosphorylated, the transcription factor is inactive and stays in the cytoplasm. When it is phosphorylated by kinase A, the transcription factor moves into the nucleus and helps turn on the transcription of a mitosis factor gene whose product stimulates cells to divide.

 

a.	The following list contains the names of the genes encoding the corresponding proteins. Which of these could potentially act as a proto-oncogene? Which might be a tumor-suppressor gene? i. growth factor ii. growth factor receptor iii. kinase A iv. transcription factor v. mitosis factor
Though it is not pictured, the cell in the figure also has a phosphatase, an enzyme that removes phosphates from proteins—in this case, from the transcription factor. This phosphatase is itself regulated by kinase A.
b.	What would you expect to be the effect when kinase A adds a phosphate group to the phosphatase? Would this activate the phosphatase enzyme or inhibit it? Explain.
c.	Is the phosphatase gene likely to be a proto-oncogene or a tumor-suppressor gene or neither?
d.	Several mutations are listed below. For each, indicate whether the mutation would lead to excessive cell growth or decreased cell growth if the cell were either homozygous for the mutation, or heterozygous for the mutation and a wild-type allele. Assume that 50% of the normal activity of all these genes is sufficient for normal cell growth. i. A null mutation in the phosphatase gene ii. A null mutation in the transcription factor gene iii. A null mutation in the kinase A gene iv. A null mutation in the growth factor receptor gene v. A mutation that causes production of a constitutively active growth factor receptor whose kinase function is active even in the absence of the growth factor vi. A mutation that causes production of a constitutively active kinase A vii. A reciprocal translocation that places the transcription factor gene downstream of a strong enhancer viii. A mutation that prevents phosphorylation of the phosphatase enzyme ix. A mutation that causes the production of a phosphatase that acts as if it is always phosphorylated