Mig6 Is a Sensor of EGF Receptor Inactivation that Directly Activates c-Abl to Induce Apoptosis during Epithelial Homeostasis

Abstract

SummaryA fundamental aspect of epithelial homeostasis is the dependence on specific growth factors for cell survival, yet the underlying mechanisms remain obscure. We found an “inverse” mode of receptor tyrosine kinase signaling that directly links ErbB receptor inactivation to the induction of apoptosis. Upon ligand deprivation Mig6 dissociates from the ErbB receptor and binds to and activates the tyrosine kinase c-Abl to trigger p73-dependent apoptosis in mammary epithelial cells. Deletion of Errfi1 (encoding Mig6) and inhibition or RNAi silencing of c-Abl causes impaired apoptosis and luminal filling of mammary ducts. Mig6 activates c-Abl by binding to the kinase domain, which is prevented in the presence of epidermal growth factor (EGF) by Src family kinase-mediated phosphorylation on c-Abl-Tyr488. These results reveal a receptor-proximal switch mechanism by which Mig6 actively senses EGF deprivation to directly activate proapoptotic c-Abl. Our findings challenge the common belief that deprivation of growth factors induces apoptosis passively by lack of mitogenic signaling.

The roles and regulation of multicellular rosette structures during morphogenesis

“…This phosphorylation is required for the planar polarized distribution of β-catenin prior to rosette formation. The upstream activator of Abl has not been identified in the context of Drosophila axis elongation, although Abl is regulated by EGF (Hopkins et al, 2012), platelet-derived growth factor (PDGF) (Brasher and Van Etten, 2000), EphA (Harbott and Nobes, 2005) and Robo (Rhee et al, 2002) in other contexts. Thus, these extracellular cues are prime candidates for activators of Abl, and hence rosette formation, during epithelial morphogenesis in Drosophila.…”

Microvesicle Cargo and Function Changes upon Induction of Cellular Transformation

“…These soluble factors then bind to their corresponding receptors expressed in a neighboring cell and induce the activation of intracellular signaling events that determine whether a cell grows, differentiates, migrates, or dies (3). These types of paracrine signaling activities are required throughout development and for tissue homeostasis, whereas deregulation of these events often leads to developmental abnormalities and the onset of diseases.…”

“…When released from a cell, EVs can function in a paracrine or endocrine manner through the transfer of their cargo to a recipient cell (3,4). This cargo is then used by the cell to elicit specific cellular processes or outcomes.…”

A pervasive role for MIG6 in restraining cell proliferation

“…In addition, Errfi1 null mice suffer from an early-onset degenerative joint disease, caused by aberrant proliferation of precursor mesenchymal cells in cartilages. [8][9][10][11][12] An unanswered question is whether these phenotypes are reflective of excess cell proliferation driven by unopposed ErbB or MET signaling. A related issue is whether it is satisfactory to rationalize the biological finalism of MIG6 induction by a plethora of stimuli solely in the context of MIG6-driven RTK inhibition.…”

“…Hopkins et al 9 set out to study mammary gland development in Errfi1 null mice. They observed an altered pattern of morphogenesis characterized by decreased ductal branching and widespread luminal filling of terminal end buds (TEBs).…”