Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

Abstract

Dynamic signals linking the actin cytoskeleton and cell adhesion receptors are essential for morphogenesis during development and normal tissue homeostasis. Abi1 is a central regulator of actin polymerization through interactions with multiple protein complexes. However, the in vivo role of Abi1 remains to be defined. The α4 integrin adhesion receptor is associated with enhanced protrusive activity and regulation of directional cell migration. Among integrin subunits, α4 exhibits unique properties in that it predominantly accumulates at the leading edge of migrating cells; however, the pathways that link the actin-regulatory machinery to α4 at the leading edge have remained elusive. We generated Abi1 KO mice and found that loss of Abi1 phenocopies KO of α4. Mice lacking Abi1 or α4 exhibit midgestational lethality with abnormalities in placental and cardiovascular development. Notably, purified Abi1 protein binds directly to the α4 cytoplasmic tail and endogenous Abi1 colocalizes with phosphorylated α4 at the leading edge of spreading cells. Moreover, Abi1-deficient cells expressing α4 have impaired cell spreading, which is rescued by WT Abi1 but not an Abi1 mutant lacking the α4-binding site. These data reveal a direct link between the α4 integrin and actin polymerization and uncover a role for Abi1 in the regulation of morphogenesis in vivo. The Abi1–α4 interaction establishes a mechanistic paradigm for signaling between adhesion events and enhanced actin polymerization at the earliest stages of protrusion.

Abelson Interactor 1 (Abi1) and Its Interaction with Wiskott-Aldrich Syndrome Protein (Wasp) Are Critical for Proper Eye Formation in Xenopus Embryos

“…Abi1 is an adaptor protein that interacts with several complexes that regulate actin dynamics, and Abi1-deficient mouse embryos die at mid-gestation with defects in the cardiovascular system, brain, and placenta, consistent with deregulation of the actin cytoskeleton and cell/cell interactions (8,9). Because Abi1, through its effects on actin dynamics, has the potential to regulate multiple complex morphogenetic events, we examined the effect of Abi1 knockdown during Xenopus embryogenesis.…”

“…In contrast, epiblast-specific disruption of Abi1 in mice caused lethality at embryonic day 11.5, and embryos displayed morphogenetic defects in the developing heart and brain because of localized impairment of actin polymerization and reduced cell migration (8). Another report noted that mice lacking Abi1 or ␣4 integrin exhibited similar phenotypes, namely mid-gestational lethality with abnormalities in placental and cardiovascular development (9). Moreover, Abi1 protein bound to phosphorylated ␣4 integrin, and this interaction was required for cell spreading in vitro, suggesting a role for Abi1 in linking ␣4 integrin to the regulation of actin dynamics to control cell movements during development (9).…”

“…binds Wave proteins, ␣4 integrin, the formin proteins Diaphanous1/2, and Nap1; or the C-terminal SH3 domain, which binds N-Wasp and c-Abl1 (5,9,18,(31)(32)(33). These constructs (wild-type abi1, abi1(⌬18 -145), or abi1 ⌬SH3) were introduced along with Abi1 MO into the D1.1.1 blastomere of embryos to test the ability of these mutants to rescue the eye defects caused by loss of Abi1.…”

“…Another report noted that mice lacking Abi1 or ␣4 integrin exhibited similar phenotypes, namely mid-gestational lethality with abnormalities in placental and cardiovascular development (9). Moreover, Abi1 protein bound to phosphorylated ␣4 integrin, and this interaction was required for cell spreading in vitro, suggesting a role for Abi1 in linking ␣4 integrin to the regulation of actin dynamics to control cell movements during development (9).…”

New Abelson interactor-1 (Abi-1)-driven mechanism of acquired drug resistance

“…21 Recent reports indicate that the N-terminus of Abi-1 interacts with the cytoplasmic tail of α4 integrin, and may mediate specific functions associated with α4-dependent processes in normal and pathological conditions. 22 Abi-1-deficient mice exhibit defects in placental and cardiovascular development leading to midgestational embryonic lethality; 22,23 these phenotypes mirror those found in mice deficient for α4 integrin or its ligand vascular cell adhesion molecule-1. 24,25 We have recently obtained evidence that Abi-1 plays a role in signaling cross talk between Bcr-Abl1 and α4 integrin.…”