Mapk Signaling As A Cancer Pathway

Signaling through the MAPK pathway composed of RAF, MEK, and ERK proteins (^■4.4) is required for the proliferation of normal cells as well as for many cancer cells. In normal cells, it typically relays signals receptor tyrosine kinases (RTKs) activated by growth factors to the nucleus, resulting in the activation of gene expression. It can also be activated by a range of other extra- and intracellular stimuli and it elicits effects besides altered gene expression. In tumor cells, MAPK signaling is often enhanced, e.g. as a consequence of oncogenic activation of RTKs or RAS (^4.4). This MAPK pathway is therefore considered as the 'classical mitogenic cascade' or as the 'canonical' pathway

In reality, this pathway is one of about six similar modules6 which each consist of a MAP kinase (like ERK1/2), a MAPK kinase (like MEK1/2), and a MAP kinase kinase (like RAF1, ARAF, or BRAF). These other MAPK modules respond likewise to extracellular signals from growth factors, but also to signals from hormones and cytokines acting through G-proteins, to cell adhesion molecules, and stress signals generated in the cell or at the cell membrane. Like the canonical pathway, these modules can stimulate cell proliferation, but also apoptosis, cell differentiation, or specific cell functions. None of them, however, has been as straightforwardly implicated in the control of cell proliferation and in cancer as the canonical pathway.

The best studied of the parallel pathways (Figure 6.1) involves MEKK1, MEK4, and JNK (JUN N-terminal kinase) leading to phosphorylation of the transcriptional

6 The number depends on how one counts incomplete modules.

Table 6.1. An overview of cancer pathways

Pathway or network Cancers involved in

Oncogene proteins in the pathway

Tumor suppressors in the pathway

Remarks

MAPK pathway (canonical) PI3K pathway

TP53 network RB1 network

TGFp pathway

JAK/STAT pathway

NFkB pathway WNT pathway

SHH pathway NOTCH pathway many many many many carcinomas, selected soft tissue cancers, selected leukemias selected carcinomas, many leukemias and lymphomas selected leukemias, many carcinomas Carcinomas of colon, liver, breast, stomach and others Specific skin, brain, and lung cancers T-cell lymphomas, carcinomas

PI3K, AKT

MDM2/HDM2 Cyclin D1, CDK4, (MYC)

PTEN, CTMP

TP53, ATM, BAX RB1, p16INK4A, p15INK4B, p57KIP2 TGFßRII, SMAD2, SMAD4, RUNX

REL proteins CYLD

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