Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppresses v-abl transforming activity.

Abstract

A novel cellular protein, Abl-interactor-1 (Abi-1), which specifically interacts with the carboxy-terminal region of Abl oncoproteins, has been identified in a mouse leukemia cell line. The protein exhibits sequence similarity to homeotic genes, contains several polyproline stretches, and includes a src homology 3 {SH3) domain at its very carboxyl terminus that is required for binding to Abl proteins. The abi-1 gene has been mapped to mouse chromosome 2 and is genetically closely linked to the c-abi locus. The gene is widely expressed in the mouse, with highest levels of mRNA found in the bone marrow, spleen, brain, and testes. The Abi-1 protein coimmunoprecipitates with v-Abl and serves as a substrate for kinase activity. When overexpressed in NIH-3T3 cells, abi-1 potently suppresses the transforming activity of Abelson leukemia virus expressing the full-length pi60^'"*^ kinase but does not affect the transforming activity of viruses expressing a truncated pPO^"*'' or \-src kinases. We suggest that the Abi-1 protein may serve as a regulator of Abl function in transformation or in signal transduction.

ENL, the MLL fusion partner in t(11;19), binds to the c-Abl interactor protein 1 (ABI1) that is fused to MLL in t(10;11)+

“…It is interesting to note that the C-terminal SH3 domain of the highly conserved mouse Abi1 was also found to be necessary, but not su cient for the binding to c-Abl. Further sequences outside of the classical SH3 motif were required for an optimal association (Shi et al, 1995). The experiments described here show that the same holds true for the binding of human ABI1 to ENL.…”

“…MLL-ABI1 was identi®ed by molecular cloning of a breakpoint cDNA from a case of acute myeloid leukemia with a t(10;11)(p11.2;q23) (Taki et al, 1998). The mouse Abi1 protein was originally isolated in a screen for proteins that are able to bind to the proto-oncoprotein c-Abl (Shi et al, 1995). The human counterpart, ABI1, is a member of a family of at least ®ve known splicing variants of the same gene.…”

“…Although this might be desirable to obtain absolute proof we feel that the combination of experiments shown here, together with the physiological link of ABI1 and ENL (both are MLL fusion partners) is strongly indicative for the physiological relevance of this association. In this respect it is important to note that the Abi1 protein was reported to be located mainly in the cytoplasm (Shi et al, 1995) whereas ENL resides in the nucleus (Rubnitz et al, 1994). However, in the case of a MLL-ABI1 fusion protein the MLL portion provides at least three nuclear localization signals that can redirect the subcellular localization of a normally cytoplasmic protein to the nucleus, as has been demonstrated in the case of the MLL-EPS15 fusion (Rogaia et al, 1997;Yano et al, 1997).…”

“…Here we report that ENL physically interacts with ABI1 that in turn was found as a MLL fusion partner in a case of acute myeloid leukemia with a t(10;11)(p11.2;q23) (Taki et al, 1998). ABI1 is a human homologue of the mouse cAbl interactor protein 1 that has been identi®ed as a binding partner of the proto-oncoprotein c-Abl (Shi et al, 1995).…”

The kinase activity of c-Abl but not v-Abl is potentiated by direct interaction with RFXI, a protein that binds the enhancers of several viruses and cell-cycle regulated genes

“…The SH2 and SH3 domains are known to mediate protein-protein interactions with speci®c tyrosine phosphorylated sequences and proline-rich motifs, respectively (Cicchetti et al, 1992;Ren et al, 1993;Cohen et al, 1995;Pawson, 1995a,b). The long C-terminal tail contains an actin binding domain (McWhirter and Wang, 1993;Van Etten et al, 1994) and several PxxP motifs capable of interacting with Crk1, Abi1 and Abi2 proteins (Ren et al, 1994;Feller et al, 1994a,b;Shi et al, 1995;Dai and Pendergast, 1995). Also, this region has a DNA binding activity Wang, 1990, 1992) with three high mobility group-like domains (Miao and Wang, 1996).…”