PMID- 17536007
OWN - NLM
STAT- MEDLINE
DCOM- 20070928
LR  - 20220321
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 21
IP  - 8
DP  - 2007 Aug
TI  - Follicle-stimulating hormone induces multiple signaling cascades: evidence that 
      activation of Rous sarcoma oncogene, RAS, and the epidermal growth factor 
      receptor are critical for granulosa cell differentiation.
PG  - 1940-57
AB  - FSH regulates ovarian granulosa cell differentiation not only by activating 
      adenylyl cyclase and protein kinase A (PKA) but also by other complex mechanisms. 
      Using primary rat granulosa cell cultures, we provide novel evidence that FSH 
      rapidly activates two small GTP-binding proteins RAP1 and RAS. FSH activation of 
      RAP1 requires cAMP-mediated activation of exchange factor activated by 
      cAMP/RAPGEF3 whereas FSH activation of RAS and downstream signaling cascades 
      involves multiple factors. Specifically, FSH activation of RAS required Rous 
      sarcoma oncogene (SRC) family tyrosine kinase (SFK) and epidermal growth factor 
      receptor (EGFR) tyrosine kinase activities but not PKA. FSH-induced 
      phosphorylation of ERK1/2 was blocked by dominant-negative RAS as well as by 
      inhibitors of EGFR tyrosine kinase, metalloproteinases involved in growth factor 
      shedding, and SFKs. In contrast, FSH-induced phosphorylation of protein kinase B 
      (PKB/AKT) and the Forkhead transcription factor, FOXO1a occurred by SFK-dependent 
      but RAS-independent mechanisms. The SFKs, c-SRC and FYN, and the SRC-related 
      tyrosine kinase ABL were present and phosphorylated rapidly in response to FSH. 
      Lastly, the EGF-like factor amphiregulin (AREG) activated RAS and ERK1/2 
      phosphorylation in granulosa cells by mechanisms that were selectively blocked by 
      an EGFR antagonist but not by an SFK antagonist. However, AREG-mediated 
      phosphorylation of PKB and FOXO1a required both EGFR and SFK activation. 
      Moreover, we show that FSH induces AREG and that activation of the EGFR impacts 
      granulosa cell differentiation and the expression of genes characteristic of the 
      luteal cell phenotype. Thus, FSH orchestrates the coordinate activation of three 
      diverse membrane-associated signaling cascades (adenylyl cyclase, RAS, and SFKs) 
      that converge downstream to activate specific kinases (PKA, ERK1/2, and 
      PKB/FOXO1a) that control granulosa cell function and differentiation.
FAU - Wayne, Chad M
AU  - Wayne CM
AD  - Department of Molecular and Cellular Biology, Baylor College of Medicine, 
      Houston, Texas 77030, USA.
FAU - Fan, Heng-Yu
AU  - Fan HY
FAU - Cheng, Xiaodong
AU  - Cheng X
FAU - Richards, Joanne S
AU  - Richards JS
LA  - eng
GR  - 5F32 HD045060/HD/NICHD NIH HHS/United States
GR  - GM66170/GM/NIGMS NIH HHS/United States
GR  - HD-16272/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070529
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 9002-68-0 (Follicle Stimulating Hormone)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/*physiology
MH  - ErbB Receptors/*genetics/metabolism
MH  - Female
MH  - Follicle Stimulating Hormone/*physiology
MH  - Granulosa Cells/*cytology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/*physiology
MH  - ras Proteins/*genetics/metabolism
EDAT- 2007/05/31 09:00
MHDA- 2007/09/29 09:00
CRDT- 2007/05/31 09:00
PHST- 2007/05/31 09:00 [pubmed]
PHST- 2007/09/29 09:00 [medline]
PHST- 2007/05/31 09:00 [entrez]
AID - me.2007-0020 [pii]
AID - 10.1210/me.2007-0020 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2007 Aug;21(8):1940-57. doi: 10.1210/me.2007-0020. Epub 2007 May 
      29.