Protein kinase signaling networks in cancer

Abstract

Protein kinases orchestrate the activation of signaling cascades in response to extracellular and intracellular stimuli to control cell growth, proliferation, and survival. The complexity of numerous intracellular signaling pathways is highlighted by the number of kinases encoded by the human genome (539) and the plethora of phosphorylation sites identified in phosphoproteomic studies. Perturbation of these signaling networks by mutations or abnormal protein expression underlies the cause of many diseases including cancer. Recent RNAi screens and cancer genomic sequencing studies have revealed that many more kinases than anticipated contribute to tumorigenesis and are potential targets for inhibitor drug development intervention. This review will highlight recent insights into known pathways essential for tumorigenesis and discuss exciting new pathways for therapeutic intervention.

Figure 1

Mechanisms of activation of the PI3K/Akt pathway in cancer. The traditional mechanism for activation of the PI3K/Akt pathway is illustrated for normal cells, where growth factors bind to their receptors (e.g. EGFR) to promote their activation and phosphorylation of targets, such as Gab1, creating phosphotyrosine-binding sites for proteins that contain SH2 domains, such as the regulatory subunit of PI3K, p85. Subsequent activation of PI3K initiates signalling through the pathway. Termination of signalling is accomplished by direct dephosphorylation of Akt by PP2A and PHLPP and elimination of the lipid second messenger PIP₃ by the lipid phosphatase PTEN. Other mechanisms to suppress signalling through this pathway include DEPTOR and PTENP1. In cancer cells mutations in these kinases or phosphatases, coupled with decreased expression of negative regulators (DEPTOR and PHLPP) promotes hyper-activation of this pathway. Filled red shapes indicate negative regulators of the pathway.

Figure 2

Targeting mutant B-RAF. Inhibitors specific for mutant B-RAF shut down signalling through the RAF-MEK-ERK pathway in cancer cells with activating mutations in B-RAF (V600E), but activate signalling through this pathway in cells with GOF RAS mutations.

Figure 3

Shedding light on a novel signalling pathway. The recent discovery that LKB1 can activate NUAK1, leading to inactivation of MYPT1 and increased MLC2 phosphorylation, suggests this pathway may be important in cancers with LKB1 LOF mutations. In cancer LKB1 LOF mutations should result in activation of MYPT1, decreased MLC-2 phosphorylation, and increased tumor cell-cell adherence, which could positively feedback to promote proliferation. LOF mutations in other kinases, such as DAPK3, could be a means for a tumor cell to reach the same end point.