title: Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction.
abstract: INSM1 is an islet transcription factor essential for pancreas development. INSM1 functions as a transcriptional repressor of NeuroD/β2 and insulin gene in the pancreas. INSM1 also possesses extra-nuclear activities through binding to multiple cellular regulators such as cyclin D1 and RACK1. In this study, we report that the interaction of INSM1 and RACK1 is essential to enhance the insulin receptor (InR)-mediated signaling pathway. A proline-rich region in the N-terminus of INSM1 is required for RACK1 binding, which interrupts RACK1-InR interaction and enhances InR signal activation. Binding of INSM1 to RACK1 increases AKT phosphorylation. The INSM1-enhanced AKT phosphorylation can be inhibited by the PI3K inhibitor, LY294002. When INSM1 induces AR42J cell trans-differentiation, the Nkx6.1 gene is activated through the InR-mediated signaling pathway and an elevation of the acetyl-H4 modification on the Nkx6.1 gene promoter/enhancer is observed. The PI3K inhibitor interrupts Nkx6.1 and insulin gene expression. Therefore, we conclude that the extra-nuclear activity of INSM1 by enhancing the PI3K/AKT signaling pathway is important for pancreatic cell differentiation.
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA.
authors.forename: Chiachen
authors.initials: C
authors.lastname: Chen
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA; Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Breslin
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA.
authors.forename: Kejing
authors.initials: K
authors.lastname: Song
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA; Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. Electronic address: mlan@chnola-research.org.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D009479:Neuropeptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D012097:Repressor Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D002867:Chromones; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D009025:Morpholines; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D000075370:Receptors for Activated C Kinase; D012097:Repressor Proteins; D014157:Transcription Factors; C477059:Insm1 protein, mouse; C491328:Nkx6-1 protein, mouse; C090294:RACK1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: INSM1; InR signaling; Nkx6.1; PI3K/AKT; RACK1