LKB1 regulates pancreatic beta cell size, polarity, and function.
Pancreatic beta cells, organized in the islets of Langerhans, sense glucose and secrete appropriate amounts of insulin. We have studied the roles of LKB1, a conserved kinase implicated in the control of cell polarity and energy metabolism, in adult beta cells. LKB1-deficient beta cells show a dramatic increase in insulin secretion in vivo. Histologically, LKB1-deficient beta cells have striking alterations in the localization of the nucleus and cilia relative to blood vessels, suggesting a shift from hepatocyte-like to columnar polarity. Additionally, LKB1 deficiency causes a 65% increase in beta cell volume. We show that distinct targets of LKB1 mediate these effects. LKB1 controls beta cell size, but not polarity, via the mTOR pathway. Conversely, the precise position of the beta cell nucleus, but not cell size, is controlled by the LKB1 target Par1b. Insulin secretion and content are restricted by LKB1, at least in part, via AMPK. These results expose a molecular mechanism, orchestrated by LKB1, for the coordinated maintenance of beta cell size, form, and function.
Granot
Zvi
Z
Department of Developmental Biology and Cancer Research and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Swisa
Avital
A
Magenheim
Judith
J
Stolovich-Rain
Miri
M
Fujimoto
Wakako
W
Manduchi
Elisabetta
E
Miki
Takashi
T
Lennerz
Jochen K
JK
Stoeckert
Christian J
CJ
Meyuhas
Oded
O
Seino
Susumu
S
Permutt
M Alan
MA
Piwnica-Worms
Helen
H
Bardeesy
Nabeel
N
Dor
Yuval
Y
D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C491654:Stk11 protein, mouse