Pi3K p110α/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport

Jing Li, Jun Song, Margaret G. Cassidy, Piotr Rychahou, Marlene E. Starr, Jianyu Liu, Xin Li, Garretson Epperly, Heidi L. Weiss, Courtney Townsend, Tianyan Gao, B. Mark Evers

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Neurotensin (NT), an intestinal peptide secreted from N cells in the small bowel, regulates a variety of physiological functions of the gastrointestinal tract, including secretion, gut motility, and intestinal growth. The class IA phosphatidylinositol 3-kinase (PI3K) family, which comprised of p110 catalytic (α,β and δ) and p85 regulatory subunits, has been implicated in the regulation of hormone secretion from endocrine cells. However, the underlying mechanisms remain poorly understood. In particular, the role of PI3K in intestinal peptide secretion is not known. Here, we show that PI3K catalytic subunit, p110α, negatively regulates NT secretion in vitro and in vivo. We demonstrate that inhibition of p110α, but not p110β, induces NT release in BON, a human endocrine cell line, which expresses NT mRNA and produces NT peptide in a manner analogous to N cells, and QGP-1, a pancreatic endocrine cell line that produces NT peptide. In contrast, overexpression of p110α decreases NT secretion. Consistently, p110α-inhibition increases plasma NT levels in mice. To further delineate the mechanisms contributing to this effect, we demonstrate that inhibition of p110α increases NT granule trafficking by up-regulating α-tubulin acetylation; NT secretion is prevented by overexpression of HDAC6, an α-tubulin deacetylase. Moreover, ras-related protein Rab27A (a small G protein) and kinase D-interacting substrate of 220 kDa (Kidins220), which are associated with NT granules, play a negative and positive role, respectively, in p110 α-inhibition-induced NT secretion. Our findings identify the critical role and novel mechanisms for the PI3K signaling pathway in the control of intestinal hormone granule transport and release.

Original languageEnglish (US)
Pages (from-to)1380-1393
Number of pages14
JournalMolecular Endocrinology
Volume26
Issue number8
DOIs
StatePublished - Aug 1 2012

Fingerprint

Intestinal Secretions
Neurotensin
Peptides
Phosphatidylinositol 3-Kinase
Endocrine Cells
Tubulin
Gastrointestinal Hormones
Cyclic GMP-Dependent Protein Kinases
ras Proteins
Cell Line
Gastrointestinal Motility
Monomeric GTP-Binding Proteins
Acetylation
Gastrointestinal Tract
Catalytic Domain

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Pi3K p110α/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport. / Li, Jing; Song, Jun; Cassidy, Margaret G.; Rychahou, Piotr; Starr, Marlene E.; Liu, Jianyu; Li, Xin; Epperly, Garretson; Weiss, Heidi L.; Townsend, Courtney; Gao, Tianyan; Mark Evers, B.

In: Molecular Endocrinology, Vol. 26, No. 8, 01.08.2012, p. 1380-1393.

Research output: Contribution to journalArticle

Li, J, Song, J, Cassidy, MG, Rychahou, P, Starr, ME, Liu, J, Li, X, Epperly, G, Weiss, HL, Townsend, C, Gao, T & Mark Evers, B 2012, 'Pi3K p110α/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport', Molecular Endocrinology, vol. 26, no. 8, pp. 1380-1393. https://doi.org/10.1210/me.2012-1024
Li, Jing ; Song, Jun ; Cassidy, Margaret G. ; Rychahou, Piotr ; Starr, Marlene E. ; Liu, Jianyu ; Li, Xin ; Epperly, Garretson ; Weiss, Heidi L. ; Townsend, Courtney ; Gao, Tianyan ; Mark Evers, B. / Pi3K p110α/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport. In: Molecular Endocrinology. 2012 ; Vol. 26, No. 8. pp. 1380-1393.
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AU - Liu, Jianyu

AU - Li, Xin

AU - Epperly, Garretson

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