Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction

Tao Zhang; Chiachen Chen; Mary B Breslin; Kejing Song; Michael S Lan

doi:10.1016/j.cellsig.2013.12.014

Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction

Cell Signal. 2014 Apr;26(4):740-7. doi: 10.1016/j.cellsig.2013.12.014. Epub 2014 Jan 7.

Authors

Tao Zhang¹, Chiachen Chen¹, Mary B Breslin², Kejing Song¹, Michael S Lan³

Affiliations

¹ The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA.
² 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.
³ 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.

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.

Keywords: INSM1; InR signaling; Nkx6.1; PI3K/AKT; RACK1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
COS Cells
Cell Line, Tumor
Chlorocebus aethiops
Chromones / pharmacology
DNA-Binding Proteins / chemistry
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Insulin / genetics
Insulin / metabolism
Mice
Molecular Sequence Data
Morpholines / pharmacology
Neuropeptides / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation / drug effects
Promoter Regions, Genetic
Protein Binding
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt / metabolism
Rats
Receptor, Insulin / metabolism
Receptors for Activated C Kinase
Repressor Proteins
Signal Transduction*
Transcription Factors / chemistry
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Chromones
DNA-Binding Proteins
Homeodomain Proteins
Insm1 protein, mouse
Insulin
Morpholines
Neuropeptides
Nkx6-1 protein, mouse
Phosphoinositide-3 Kinase Inhibitors
RACK1 protein, mouse
Receptors for Activated C Kinase
Repressor Proteins
Transcription Factors
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Receptor, Insulin
Proto-Oncogene Proteins c-akt

Abstract

Publication types

MeSH terms

Substances

Grants and funding