Glucose‐regulated protein 78 (GRP78) binds directly to PIP₃ phosphatase SKIP and determines its localization

Abstract

Skeletal muscle and kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP 3 phosphatase, has been implicated in the regulation of insulin signaling in skeletal muscle. SKIP interacts with

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

“…nase (PI3K) signaling, 15 suggesting a possible overlap with the function of the MSS-associated gene SIL1.…”

“…32 It is possible that changes in AKT-mTOR activity in the brain will contribute to cognitive deficits as this signaling pathway has been found disrupted in multiple neurodevelopmental disorders. 33 In addition, INPP5K's signaling activity is directly regulated by its binding partner HSPA5/BiP, 15,34 which is in turn regulated by the MSS-associated gene SIL1. 11 SIL1 regulates the activation stage of HSPA5/BiP in the ER and BiP is a critical chaperone for trafficking of glycoproteins.…”

The phosphoinositide 5-phosphatase INPP5K: From gene structure to in vivo functions

“…As mentioned above, at the cytosolic side of the ER membrane, INPP5K binds to the N-terminal region of ARL6IP1 which protrudes in the cytosol (Dong et al, 2018). Interaction of INPP5K with luminal ER GRP78 has also been described, but the molecular mechanism is still unresolved (Ijuin et al, 2016). It is noteworthy here that mammalian INPP5K shares this ER localization with the yeast phosphoinositide 5-phosphatase Inp54p.…”

“…Ijuin and collaborators proposed a model in which, in basal conditions, cytosolic INPP5K directly interacts via its SKICH domain with GRP78/Glucose regulated protein 78, a luminal ER chaperone protein involved in ER stress and the UPR (Ijuin and Takenawa, 2012b, 2015a, 2015b, 2015cand 2016. However, in this model, the unresolved issue is how INPP5K which is present in the cytosol and at the cytosolic side of the ER membrane interacts with luminal ER GRP78 (Ijuin et al, 2016). After insulin stimulation, the INPP5K-GRP78 complex migrates from ER to the plasma membrane, where activated PAK1/p21-activated protein kinase 1 competitively binds through a 11 amino-acids peptide within its kinase domain to INPP5K in place of GRP78, linking INPP5K to the complex of proteins associated with the insulin receptor.…”

“…After growth factor or insulin stimulation, INPP5K is transiently translocated from the ER to the plasma membrane, where it could bind to activated PAK1, SODD or still undefined plasma membrane ligands via its SKICH domain (see above). At the plasma membrane, INPP5K co-localizes with submembranous actin at the leading edge of the cell, specifically at membrane ruffles (Gurung et al, 2003;Ijuin and Takenawa, 2003, 2012b, 2016. Finally, Ramos and collaborators recently reported that INPP5K, beside its known ER, plasma membrane and cytosolic localizations, is also present in the nucleus of the human U-251 malignant glioblastoma (MG) cell line (Ramos et al, 2020).…”