TY - JOUR
T1 - Deficient E-cadherin adhesion in C57BL/6J-Min/+ mice is associated with increased tyrosine kinase activity and RhoA-dependent actomyosin contractility
AU - Carothers, Adelaide M.
AU - Javid, Sara H.
AU - Moran, Amy E.
AU - Hunt, Daniel H.
AU - Redston, Mark
AU - Bertagnolli, Monica M.
N1 - Funding Information:
This work was supported by NCI Grant R29CA74162 from the National Institutes of Health (M.M.B.), the Irving Weinstein Foundation (A.M.C.), and the National Institutes of Health Surgical Oncology Research Training Grants T32-CA68971 (D.H.H.) and T32-CA09535 (S.H.J.). We thank Lee Cohen-Gould of the Department of Cell Biology at Weill College of Medicine of Cornell University for her excellent assistance in performing the transmission electron microscopy.
PY - 2006/2/15
Y1 - 2006/2/15
N2 - The Min/+ mouse is a model for APC-dependent colorectal cancer (CRC). We showed that tumorigenesis in this animal was associated with decreased E-cadherin adhesion and increased epidermal growth factor receptor (Egfr) activity in the non-tumor intestinal mucosa. Here, we tested whether these abnormalities correlated with changes in the actin cytoskeleton due to increased Rho-ROCK signaling. We treated Apc+/+ (WT) littermate small intestine with EGTA, an inhibitor of E-cadherin, and with LPA, an RhoA activator; both induced effects on adhesion and kinase activity that mimicked the Min/+ phenotype. GTP-bound Rho was increased in Min/+ enterocytes relative to WT. Since RhoA activity is associated with actomyosin contractility, markers of this signaling cascade were assessed including phosphorylated myosin light chain (MLC), cofilin, Pyk2, Src, and MAPK kinases. The increased actomyosin contractility characterizing Min/+ intestinal tissue was suppressed by the ROCK inhibitor, Y27632, but was inducible in the WT by EGTA or LPA. Finally, ultrastructural imaging revealed changes consistent with actomyosin contractility in Min/+ enterocytes. Thus, the positive regulation of E-cadherin adhesion provided by Apc+ in vivo allows proper negative regulation of Egfr, Src, Pyk2, and MAPK, as well as RhoA activities.
AB - The Min/+ mouse is a model for APC-dependent colorectal cancer (CRC). We showed that tumorigenesis in this animal was associated with decreased E-cadherin adhesion and increased epidermal growth factor receptor (Egfr) activity in the non-tumor intestinal mucosa. Here, we tested whether these abnormalities correlated with changes in the actin cytoskeleton due to increased Rho-ROCK signaling. We treated Apc+/+ (WT) littermate small intestine with EGTA, an inhibitor of E-cadherin, and with LPA, an RhoA activator; both induced effects on adhesion and kinase activity that mimicked the Min/+ phenotype. GTP-bound Rho was increased in Min/+ enterocytes relative to WT. Since RhoA activity is associated with actomyosin contractility, markers of this signaling cascade were assessed including phosphorylated myosin light chain (MLC), cofilin, Pyk2, Src, and MAPK kinases. The increased actomyosin contractility characterizing Min/+ intestinal tissue was suppressed by the ROCK inhibitor, Y27632, but was inducible in the WT by EGTA or LPA. Finally, ultrastructural imaging revealed changes consistent with actomyosin contractility in Min/+ enterocytes. Thus, the positive regulation of E-cadherin adhesion provided by Apc+ in vivo allows proper negative regulation of Egfr, Src, Pyk2, and MAPK, as well as RhoA activities.
KW - APC-dependent colon cancer
KW - Actomyosin contractility
KW - E-cadherin-mediated cell-cell adhesion
KW - MAP kinase
KW - RhoA
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U2 - 10.1016/j.yexcr.2005.11.019
DO - 10.1016/j.yexcr.2005.11.019
M3 - Article
C2 - 16368433
AN - SCOPUS:29144502281
SN - 0014-4827
VL - 312
SP - 387
EP - 400
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 4
ER -