PIPKIγi5 regulates the endosomal trafficking and degradation of E-cadherin

Abstract

BSTRACTPhosphatidylinositol phosphate kinases (PIPKs) have distinct cellular targeting, allowing for site-specific synthesis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] to activate specific signaling cascades required for cellular processes. Several C-terminal splice variants of PIPKIc (also known as PIP5K1C) exist, and have been implicated in a multitude of cellular roles. PI(4,5)P 2 serves as a fundamental regulator of E-cadherin transport, and PI(4,5)P 2 -generating enzymes are important signaling relays in these pathways. We present evidence that the isoform 5 splice variant of PIPKIc (PIPKIci5) associates with E-cadherin and promotes its lysosomal degradation. Additionally, we show that the endosomal trafficking proteins SNX5 and SNX6 associate with PIPKIci5 and inhibit PIPKIci5-mediated Ecadherin degradation. Following HGF stimulation, activated Src directly phosphorylates PIPKIci5. Phosphorylation of the PIPKIci5 Cterminus regulates its association with SNX5 and, consequently, Ecadherin degradation. Additionally, this PIPKIci5-mediated pathway requires Rab7 to promote degradation of internalized E-cadherin. Taken together, the data indicate that PIPKIci5 and SNX5 are crucial regulators of E-cadherin sorting and degradation. PIPKIci5, SNX and phosphoinositide regulation of lysosomal sorting represent a novel area of PI(4,5)P 2 signaling and research. PIPKIci5 regulation of E-cadherin sorting for degradation might have broad implications in development and tissue maintenance, and enhanced PIPKIci5 function might have pathogenic consequences due to downregulation of E-cadherin.

On the move: endocytic trafficking in cell migration

“…The ubiquitylation is recognized by the ESCRT-0 complex protein Hrs which recruits ESCRT machinery to catalyze the intraluminal sorting of the ubiquitylated cargo [110]. This degradative pathway was recently shown to be promoted by association of isoform 5 splice variant of PIPKIc (PIPKIci5) with E-cadherin [111] in a phosphorylation-dependent manner. SNX5 and SNX6 were reported to associate with PIPKIci5 and to inhibit PIPKIci5-mediated E-cadherin degradation.…”

“…SNX5 and SNX6 were reported to associate with PIPKIci5 and to inhibit PIPKIci5-mediated E-cadherin degradation. Src-induced phosphorylation of PIPKIci5 downstream of HGF signaling impaired SNX5 binding thereby relieving the inhibition of PIPKIci5-driven E-cadherin degradation [111]. The exact mechanism behind this regulation remains to be determined.…”

Emerging roles of PtdIns(4,5)P2 – beyond the plasma membrane

“…2) (Schill and Anderson, 2009b;Sun et al, 2013a,b). At the endosome, PIPKIγi5 -through its unique C-tail -directly associates with the two targeting proteins SNX5 and LAPTM4B, both of which are PtdIns(4,5)P 2 effectors (Schill et al, 2014;Sun et al, 2013b;Tan et al, 2015a). SNX5 belongs to the phosphoinositide-binding Phox (PX)-homologydomain-containing protein family that is involved in various membrane trafficking processes (van Weering et al, 2010).…”

“…All PIPKIγ isoforms directly bind E-cadherin through the conserved kinase domain, and PIPKIγi2 binds and regulates E-cadherin trafficking to and from the plasma membrane (Schill and Anderson, 2009a), which will be discussed below. PIPKIγi5 also regulates lysosomal sorting and degradation of E-cadherin, although this is less well defined (Schill et al, 2014). In this pathway, PIPKIγi5 directly binds and promotes E-cadherin sorting to the late endosome and/or lysosome compartments, but SNX5 appears to inhibit E-cadherin degradation by an unknown mechanism (Schill et al, 2014).…”

“…PIPKIγi5 also regulates lysosomal sorting and degradation of E-cadherin, although this is less well defined (Schill et al, 2014). In this pathway, PIPKIγi5 directly binds and promotes E-cadherin sorting to the late endosome and/or lysosome compartments, but SNX5 appears to inhibit E-cadherin degradation by an unknown mechanism (Schill et al, 2014). The ESCRT complex is also known to regulate the lysosomal sorting of ubiquitylated E-cadherin (Palacios et al, 2005), but how it collaborates with PIPKIγi5-mediated PtdIns(4,5)P 2 signaling in E-cadherin sorting needs further investigation.…”