Question

Why would overexpression of RTK (Receptor Tyrosine Kinase) lead to an oncogenic phenotype (describe the mechanism)?

Answer 1

MAP kinase pathway involves Receptor Tyrosine Kinase . If this signalling pathway is overexpressed, cancer may be caused. The pathway is described below:

In MAP kinase pathway growth hormones or growth factors, such as Epidermal Growth Factor (EGF), Platelet Derived Growth Factor (PDGF) acts as extracellular signals. When this ligand bind with Receptor Tyrosine Kinase receptor such as EGFR (Epidermal Growth Factor Receptor), the monomer of receptor get dimerized and become activated. Then Receptor activates various proteins such as Grb2. Grb2 then activates SOS protein by phosphorylation. SOS protein in turn activates RAS protein. In its inactive state RAS remain associated with GDP. SOS replaces this GDP with GTP and thus RAS becomes activated. Activated RAS then add phosphate group to RAF protein . This RAF is also called MAPKKK (MAP kinase kinase kinase). MAPKKK in turn activates MEK 1/2 protein. MEK 1/2 is also known as MAP Kinase Kinase (MAPKK). MEK 1/ 2 in turn activates ERK 1/2 protein by phosphorylation. ERK 1 /2 is also known as MAP Kinase (MAPK). Then ERK 1/2 activates various transcription factors such as fos , jun, myc etc. These transcription factors enters the nucleus and binds with DNA and regulates the expression of the genes required for the production of growth factors, cyclin, CDKs and any other proteins required for cell proliferation. If there is any mutation in RTK, then they activated the downstream molecules continuously without any induction. As a result the proteins required for cell proliferation are expressed continuously and this lead to uncontrolled cell proliferation leading to cancer.