PI3K p110α/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport.
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 p110α-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.
Department of Surgery, University of Kentucky, Lexington, Kentucky, USA.
Jing
J
Li
Jun
J
Song
Margaret G
MG
Cassidy
Piotr
P
Rychahou
Marlene E
ME
Starr
Jianyu
J
Liu
Xin
X
Li
Garretson
G
Epperly
Heidi L
HL
Weiss
Courtney M
CM
Townsend
Tianyan
T
Gao
B Mark
BM
Evers
D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009496:Neurotensin / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011744:Pyrimidinones / Q000494:pharmacology; D055571:Secretory Pathway; D022142:Secretory Vesicles / Q000502:physiology*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
D006835:Hydrazones; C482591:KIDINS220 protein, human; D008565:Membrane Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; C549211:PIK 75; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D013449:Sulfonamides; C504718:TGX 221; D014404:Tubulin; D000075745:rab27 GTP-Binding Proteins; D009496:Neurotensin; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins