Question

A mutation in the Ras protein renders Ras constitutively active (RasD). 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-kB?

Answer 1

Answer:

Constitutive activation is the alteration of a protein or signaling pathway such that it is functional or engaged even in the absence of an upstream activating event. For example, RasD is constitutively active because it cannot bind GAP and therefore remains in the GTP-bound, active state even when cells are not stimulated by growth factor to activate a receptor tyrosine kinase.

Constitutively active Ras is cancer promoting because cells will proliferate in the absence of growth factors, and thus normal regulatory mechanisms for cell proliferation are bypassed.

(a) A mutation that resulted in Smad3 binding Smad4, entering the nucleus, and activating transcription independent of phosphorylation by the TGFβ receptor would render Smad3 constitutively active.

(b) A mutation that made MAPK active as a kinase and able to enter the nucleus without being phosphorylated by MEK would render MAPK constitutively active.

(c) A mutation that prevented NF-KB from binding to IK-B or that allowed NF-KB to enter the nucleus and regulate transcription even when bound to IK-B would render NF-KB constitutively active.