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4 results on '"Pyk2"'

1. FAK/PYK2 promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β.

Author

Gao, Chenxi, Chen, Guangming, Kuan, Shih-Fan, Zhang, Dennis Han, Schlaepfer, David D, and Hu, Jing

Subjects
Animals, Mice, Inbred C57BL, Humans, Mice, Mice, Nude, Colorectal Neoplasms, Glycogen Synthase Kinase 3, Gene Expression Regulation, Female, Focal Adhesion Kinase 1, Focal Adhesion Kinase 2, Wnt Signaling Pathway, Carcinogenesis, Glycogen Synthase Kinase 3 beta, FAK, GSK3, PYK2, Wnt/b-catenin pathway, biochemistry, cell biology, human, intestinal tumorigenesis, mouse, phosphorylation, Inbred C57BL, Nude, Digestive Diseases, Cancer, Colo-Rectal Cancer, 2.1 Biological and endogenous factors, Biochemistry and Cell Biology
Abstract

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.

Published
2015

2. FAK/PYK2 promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β

Author

Gao, Chenxi, Chen, Guangming, Kuan, Shih-Fan, Zhang, Dennis Han, Schlaepfer, David D, and Hu, Jing

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Digestive Diseases, Colo-Rectal Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Carcinogenesis, Colorectal Neoplasms, Female, Focal Adhesion Kinase 1, Focal Adhesion Kinase 2, Gene Expression Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Mice, Mice, Inbred C57BL, Mice, Nude, Wnt Signaling Pathway, FAK, GSK3, PYK2, Wnt/b-catenin pathway, biochemistry, cell biology, human, intestinal tumorigenesis, mouse, phosphorylation, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

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.

Published
2015

3. Targeting Pyk2 to β1-Integrin–Containing Focal Contacts Rescues Fibronectin-Stimulated Signaling and Haptotactic Motility Defects of Focal Adhesion Kinase–Null Cells

Author

Klingbeil, Candice K, Hauck, Christof R, Hsia, Datsun A, Jones, KC, Reider, Shannon R, and Schlaepfer, David D

Subjects
Biochemistry and Cell Biology, Biological Sciences, Animals, Cell Movement, Cells, Cultured, Cytoskeletal Proteins, Enzyme Activation, Fibroblasts, Fibronectins, Focal Adhesion Kinase 1, Focal Adhesion Kinase 2, Focal Adhesion Protein-Tyrosine Kinases, Gene Expression, Humans, Integrin beta1, JNK Mitogen-Activated Protein Kinases, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Paxillin, Phosphoproteins, Protein-Tyrosine Kinases, Recombinant Fusion Proteins, Signal Transduction, FAK, Pyk2, cell migration, integrins, signaling, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Focal adhesion kinase-null (FAK(-/-) fibroblasts exhibit morphological and motility defects that are reversed by focal adhesion kinase (FAK) reexpression. The FAK-related kinase, proline-rich tyrosine kinase 2 (Pyk2), is expressed in FAK(-/-) cells, yet it exhibits a perinuclear distribution and does not functionally substitute for FAK. Chimeric Pyk2/FAK proteins were created and expressed in FAK(-/-) cells to determine the impact of Pyk2 localization to focal contacts. Whereas an FAK/Pyk2 COOH-terminal (CT) domain chimera was perinuclear distributed, stable expression of a Pyk2 chimera with the FAK-CT domain (Pyk2/FAK-CT) localized to focal contact sites and enhanced fibronectin (FN)-stimulated haptotactic cell migration equal to FAK-reconstituted cells. Disruption of paxillin binding to the FAK-CT domain (S-1034) inhibited Pyk2/FAK-CT localization to focal contacts and its capacity to promote cell motility. Paxillin binding to the FAK-CT was necessary but not sufficient to mediate the indirect association of FAK or Pyk2/FAK-CT with a beta 1-integrin-containing complex. Both FAK and Pyk2/FAK-CT but not Pyk2/FAK-CT S-1034 reconstituted FAK(-/-) cells, exhibit elevated FN-stimulated extracellular signal-regulated kinase 2 (ERK2) and c-Jun NH(2)-terminal kinase (JNK) kinase activation. FN-stimulated FAK or Pyk2/FAK-CT activation enhanced both the extent and duration of FN-stimulated ERK2 activity which was necessary for cell motility. Transient overexpression of the FAK-CT but not FAK-CT S-1034 domain inhibited both FN-stimulated ERK2 and JNK activation as well as FN-stimulated motility of Pyk2/FAK-CT reconstituted cells. These gain-of-function studies show that the NH(2)-terminal and kinase domains of Pyk2 can functionally substitute for FAK in promoting FN-stimulated signaling and motility events when localized to beta-integrin-containing focal contact sites via interactions mediated by the FAK-CT domain.

Published
2001

4. Targeting Pyk2 to beta 1-integrin-containing focal contacts rescues fibronectin-stimulated signaling and haptotactic motility defects of focal adhesion kinase-null cells.

Author

Klingbeil, CK, Hauck, CR, Hsia, DA, Jones, KC, Reider, SR, and Schlaepfer, DD

Subjects
Cells, Cultured, Fibroblasts, Animals, Mice, Knockout, Humans, Mice, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 1, JNK Mitogen-Activated Protein Kinases, Cytoskeletal Proteins, Fibronectins, Phosphoproteins, Recombinant Fusion Proteins, Signal Transduction, Cell Movement, Gene Expression, Enzyme Activation, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesion Kinase 1, Focal Adhesion Kinase 2, Paxillin, Protein-Tyrosine Kinases, Integrin beta1, FAK, Pyk2, cell migration, integrins, signaling, Cells, Cultured, Knockout, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Focal adhesion kinase-null (FAK(-/-) fibroblasts exhibit morphological and motility defects that are reversed by focal adhesion kinase (FAK) reexpression. The FAK-related kinase, proline-rich tyrosine kinase 2 (Pyk2), is expressed in FAK(-/-) cells, yet it exhibits a perinuclear distribution and does not functionally substitute for FAK. Chimeric Pyk2/FAK proteins were created and expressed in FAK(-/-) cells to determine the impact of Pyk2 localization to focal contacts. Whereas an FAK/Pyk2 COOH-terminal (CT) domain chimera was perinuclear distributed, stable expression of a Pyk2 chimera with the FAK-CT domain (Pyk2/FAK-CT) localized to focal contact sites and enhanced fibronectin (FN)-stimulated haptotactic cell migration equal to FAK-reconstituted cells. Disruption of paxillin binding to the FAK-CT domain (S-1034) inhibited Pyk2/FAK-CT localization to focal contacts and its capacity to promote cell motility. Paxillin binding to the FAK-CT was necessary but not sufficient to mediate the indirect association of FAK or Pyk2/FAK-CT with a beta 1-integrin-containing complex. Both FAK and Pyk2/FAK-CT but not Pyk2/FAK-CT S-1034 reconstituted FAK(-/-) cells, exhibit elevated FN-stimulated extracellular signal-regulated kinase 2 (ERK2) and c-Jun NH(2)-terminal kinase (JNK) kinase activation. FN-stimulated FAK or Pyk2/FAK-CT activation enhanced both the extent and duration of FN-stimulated ERK2 activity which was necessary for cell motility. Transient overexpression of the FAK-CT but not FAK-CT S-1034 domain inhibited both FN-stimulated ERK2 and JNK activation as well as FN-stimulated motility of Pyk2/FAK-CT reconstituted cells. These gain-of-function studies show that the NH(2)-terminal and kinase domains of Pyk2 can functionally substitute for FAK in promoting FN-stimulated signaling and motility events when localized to beta-integrin-containing focal contact sites via interactions mediated by the FAK-CT domain.

Published
2001

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