Ready and Abl

As most tyrosine kinases need to be activated to elicit a downstream response, understanding the mechanism of activation is of fundamental importance. Surprisingly, the activation of the oncogenic tyrosine kinase, c-Abl, has remained undiscovered for the past 20 years. In this month's issue of Nature Cell Biology, Ann Marie Pendergast and colleagues unravel some of this elusive activation mechanism.

c-Abl is localized to many cellular compartments and seems to be regulated through numerous external stimuli. Whilst the kinase has effects on diverse processes such as cell proliferation, cell death, migration, the cytoskeleton and gene expression, the work by Pendergast and colleagues indicates how the protein is activated during platelet-derived growth factor (PDGF) stimulation, including chemotaxis.

Cell lines expressing mutant forms of the PDGFR (platelet-derived growth factor receptor) lack c-Abl activation in response to PDGF. This activation could be restored after transfection of a receptor subunit that can bind the downstream effector phospholipase C (PLC)γ. Inhibitors of PLCγ prevent an increase in c-Abl activity. Chemotaxis towards a source of PDGF is known to increase PLCγ activity, whilst PLCγ overexpression can potentiate cell movement towards a PDGF source. This effect on chemotaxis is enhanced in cells expressing activated c-Abl and inhibited by kinase-inactive c-Abl.

Following activation by PDGF, PLCγ hydrolyses phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂). The authors found that depleting PtdIns(4,5)P₂ also increased c-Abl activity. PtdIns(4,5)P₂ seems to bind to the SH2-SH1 (Src-homology) domains in c-Abl, which presents a direct means for inhibiting enzyme activity. How this inhibition of c-Abl is regulated is not yet known, but the authors propose that, through PDGF signalling, PtdIns(4,5)P₂ binding would be abrogated, allowing c-Abl to be activated.

Other results did surprise the authors, especially the identification of a cellular complex of PLCγ and c-Abl. But more surprising still was the identification of PLCγ as a phosphorylation target for activated c-Abl in vivo. c-Abl complexes more tightly with PLCγ when it is active and through phosphorylation can inhibit the function of PLCγ, so forming an activation feedback loop.

Although this mechanism of activation of c-Abl will not be universal, it is the first link between c-Abl and phosphoinositide signalling, and has uncovered one new way in which to control activation of this tyrosine kinase. The work also shows how chemotaxis of cells towards a PDGF source requires active c-Abl. As c-Abl and PLCγ regulate the activity of one another, this work does not simplify the known roles of c-Abl, but further complicates the understanding of this kinase. Nothing in life ever seems easy, and c-Abl seems to need more than one mechanism to ensure it is ready for activation.