Multifunctional Abl kinases in health and disease

Abstract

The Abelson tyrosine kinases were initially identified as drivers of leukemia in mice and humans. The Abl family kinases Abl1 and Abl2 regulate diverse cellular processes during development and normal homeostasis, and their functions are subverted during inflammation, cancer and other pathologies. Abl kinases can be activated by multiple stimuli leading to cytoskeletal reorganization required for cell morphogenesis, motility, adhesion and polarity. Depending on the cellular context, Abl kinases regulate cell survival and proliferation. Emerging data support important roles for Abl kinases in pathologies linked to inflammation. Among these are neurodegenerative diseases and inflammatory pathologies. Unexpectedly, Abl kinases have also been identified as important players in mammalian host cells during microbial pathogenesis. Thus, the use of Abl kinase inhibitors might prove to be effective in the treatment of pathologies beyond leukemia and solid tumors. In this Cell Science at a Glance article and in the accompanying poster, we highlight the emerging roles of Abl kinases in the regulation of cellular processes in normal cells and diverse pathologies ranging from cancer to microbial pathogenesis.

Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2

“…Moreover, tyrosine phosphorylation levels of endogenous RUNX2 and TAZ were reduced in ABL-depleted primary murine osteoblasts, with loss in the assembly of the RUNX2-TAZ complex and a concomitant loss of the transcriptional activity of this complex ( Figure 2, I and J). homolog 1) (17,18), is essential for normal bone formation, as Sh3bp2 -/-mice display osteoporosis due to defective osteoblastogenesis (19). We have demonstrated that endogenous ABL kinase is activated by 3BP2 in osteoblasts and that the ectopic expression of ABL rescued the defective mineralization observed in 3BP2-depleted osteoblasts (19).…”

Inactivation of ABL kinases suppresses non–small cell lung cancer metastasis

“…Thus, ABL kinases may function as integrator kinases downstream of diverse oncogenic mutations. ABL kinases are activated downstream of multiple RTKs (6,40). Following activation, the ABL kinases often promote phosphorylation of the activating RTK and engage in bidirectional signaling that may result in decreased internalization of the receptor (41).…”

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

“…The Abl kinase is involved in a number of signaling pathways that control cell growth, survival, invasion, adhesion and migration 1–5 . In Abl 6–8 , as in the other human cytoplasmic tyrosine kinases 9,10 , inhibition and activation is regulated allosterically through intramolecular interactions involving modular domains such as the SH3, SH2 and the kinase domain (KD) (Fig.…”