title: Phosphoprotein Phosphatase 1 Is Required for Extracellular Calcium-Induced Keratinocyte Differentiation.
abstract: Extracellular calcium is a major regulator of keratinocyte differentiation in vitro and appears to play that role in vivo, but the mechanism is unclear. We have previously demonstrated that, following calcium stimulation, PIP5K1α is recruited by the E-cadherin-β-catenin complex to the plasma membrane where it provides the substrate PIP2 for both PI3K and PLC-γ1. This signaling pathway is critical for calcium-induced generation of second messengers including IP3 and intracellular calcium and keratinocyte differentiation. In this study, we explored the upstream regulatory mechanism by which calcium activates PIP5K1α and the role of this activation in calcium-induced keratinocyte differentiation. We found that treatment of human keratinocytes in culture with calcium resulted in an increase in serine dephosphorylation and PIP5K1α activation. PP1 knockdown blocked extracellular calcium-induced increase in serine dephosphorylation and activity of PIP5K1α and induction of keratinocyte differentiation markers. Knockdown of PLC-γ1, the downstream effector of PIP5K1α, blocked upstream dephosphorylation and PIP5K1α activation induced by calcium. Coimmunoprecipitation revealed calcium induced recruitment of PP1 to the E-cadherin-catenin-PIP5K1α complex in the plasma membrane. These results indicate that PP1 is recruited to the extracellular calcium-dependent E-cadherin-catenin-PIP5K1α complex in the plasma membrane to activate PIP5K1α, which is required for PLC-γ1 activation leading to keratinocyte differentiation.
authors.affiliation: Institute of Endocrinology and Metabolism, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
authors.forename: Chandrama
authors.identifier: 0000-0002-5653-9887
authors.initials: C
authors.lastname: Shrestha
authors.affiliation: Institute of Endocrinology and Metabolism, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
authors.forename: Yuanyuan
authors.identifier: 0000-0003-3956-5685
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Institute of Endocrinology and Metabolism, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Fan
authors.affiliation: Institute of Endocrinology and Metabolism, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
authors.forename: Lusha
authors.identifier: 0000-0003-1863-8603
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Endocrinology and Metabolism, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, CA 94121, USA.
authors.forename: Sally D
authors.initials: SD
authors.lastname: Pennypacker
authors.affiliation: Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, CA 94121, USA.
authors.forename: Daniel D
authors.identifier: 0000-0002-1040-475X
authors.initials: DD
authors.lastname: Bikle
authors.affiliation: Institute of Endocrinology and Metabolism, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, CA 94121, USA.
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Xie
mesh_terms: D015820:Cadherins / Q000235:genetics; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics*; D054645:Protein Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics
chemical_list: D015820:Cadherins; D017476:Receptors, Neuropeptide Y; D051176:beta Catenin; C109491:neuropeptide Y4 receptor; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D054645:Protein Phosphatase 1; D051966:Phospholipase C gamma; D002118:Calcium