The amphiphysin-like protein 1 (ALP1) interacts functionally with the cABL tyrosine kinase and may play a role in cytoskeletal regulation

Abstract

ABSTRACTcABL is a protooncogene, activated in a subset of human leukemias, whose protein product is a nonreceptor tyrosine kinase of unknown function. cABL has a complex structure that includes several domains and motifs found in proteins implicated in signal transduction pathways. An approach to elucidate cABL function is to identify proteins that interact directly with cABL and that may serve as regulators or effectors of its activity. To this end, a proteininteraction screen of a phage expression library was undertaken to identify proteins that interact with specific domains of cABL. An SH3-domain-containing protein has been identified that interacts with sequences in the cABL carboxyl terminus. The cDNA encoding ALP1 (amphiphysin-like protein 1) was isolated from a 16-day mouse embryo. ALP1 has high homology to BIN1, a recently cloned myc-interacting protein, and also shows significant homology to amphiphysin, a neuronal protein cloned from human and chicken. The amino terminus has homology to two yeast proteins, Rvs167 and Rvs161, which are involved in cell entry into stationary phase and cytoskeletal organization. ALP1 binds cABL in vitro and in vivo. Expression of ALP1 results in morphological transformation of NIH 3T3 fibroblasts in a cABL-dependent manner. The properties of ALP1 suggest that it may be involved in possible cytoskeletal functions of the cABL kinase. Additionally, these results provide further evidence for the importance of the cABL carboxyl terminus and its binding proteins in the regulation of cABL function.

Inhibition of Cell Migration by Abl Family Tyrosine Kinases through Uncoupling of Crk-CAS Complexes

“…The Drosophila homologue of mammalian Abl, D-Abl, is also responsible for regulating actin dynamics and cell adhesion of neurons (5,49,50). This is consistent with observations that ablϪ/Ϫ argϪ/Ϫ mice show lethal defects in neurulation and changes in their actin cytoskeleton (3).…”

“…Recent evidence suggests that Abl family kinases regulate the actin cytoskeleton and influence cell morphology (2)(3)(4)(5)(6)(7)(8). However, the biological significance of this is not clear.…”

“…Coordination of simultaneous binding of Abl to G-and F-actin is thought to aid in the bundling of actin filaments (13). The cytoskeletal-associated proteins, amphiphysin-like protein 1 (ALP1) and Abl/ Arg-binding protein 2 (ArgBP2), also bind Abl family enzymes (5,6), providing a mechanism of indirect interaction between Abl family kinases and the cytoskeleton. In addition, fusion of Bcr to Abl creates Bcr-Abl, which primarily localizes to the cytoskeleton in the cytoplasm and is strongly associated with cell transformation and leukemia (14,15).…”

The amphiphysin family of proteins and their role in endocytosis at the synapse

“…A very recent study reported an interaction between the tyrosine kinase c-Abl and ALP-1, an Amph2 splice variant with a broad tissue distribution 49 . The interaction occurs through the SH3 domain of ALP-1.…”

The pathobiology of the septin gene family

“…For example, several endocytosis proteins such as Eps15, CALM/AP180, and endophilins such as SH3p8 have been translocation partners of MLL [162]. In addition, splice variants of amphiphysin can interact with c-abl or myc to enhance their transforming activities [163,164] and can also be a tumour-associated (paraneoplastic) autoantigen [165]. Adaptins have also been reported to be deleted in some tumours [166]; the TSC2 gene (responsible for tuberous sclerosis) is a biochemical and functional partner of Rab5, a GTPase involved in the endocytic pathway [167]; and β-adaptin is reported to bind a cancer critical gene, ATM [168].…”