FAK/PYK2 promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β.
Aberrant activation of Wnt/β-catenin signaling plays an unequivocal role in colorectal cancer, but identification of effective Wnt inhibitors for use in cancer remains a tremendous challenge. New insights into the regulation of this pathway could reveal new therapeutic point of intervention, therefore are greatly needed. Here we report a novel FAK/PYK2/GSK3β(Y216)/β-catenin regulation axis: FAK and PYK2, elevated in adenomas in APC(min/+) mice and in human colorectal cancer tissues, functioned redundantly to promote the Wnt/β-catenin pathway by phosphorylating GSK3β(Y216) to reinforce pathway output-β-catenin accumulation and intestinal tumorigenesis. We previously showed that Wnt-induced β-catenin accumulation requires Wnt-induced GSK3β/β-TrCP interaction; the current study revealed that phosphorylation of GSK3β(Y216) was a molecular determinant of GSK3β recruitment of β-TrCP. Pharmacological inhibition of FAK/PYK2 suppressed adenoma formation in APC(min/+) mice accompanied with reduced intestinal levels of phospho-GSK3β(Y216) and β-catenin, indicating that FAK/PYK2/GSK3β(Y216) axis is critical for the activation of Wnt/β-catenin signaling in APC driven intestinal tumorigenesis.
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States.
Chenxi
C
Gao
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States.
Guangming
G
Chen
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States.
Shih-Fan
SF
Kuan
Dietrich School of Arts and Sciences, Pittsburgh, United States.
Dennis Han
DH
Zhang
Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, San Diego, United States.
David D
DD
Schlaepfer
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States.
Jing
J
Hu
D000818:Animals; D063646:Carcinogenesis; D015179:Colorectal Neoplasms / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D060449:Wnt Signaling Pathway
D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
FAK; GSK3; PYK2; Wnt/b-catenin pathway; biochemistry; cell biology; human; intestinal tumorigenesis; mouse; phosphorylation