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Vol. 20, Issue 20, 4324-4334, October 15, 2009

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Protein Tyrosine Phosphatase Epsilon Regulates Integrin-mediated Podosome Stability in Osteoclasts by Activating Src

Shira Granot-Attas^*, Chen Luxenburg^,, Eynat Finkelshtein^*, and Ari Elson^*

Department of *Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel and Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel

Submitted December 1, 2008; Revised July 13, 2009; Accepted August 11, 2009
Monitoring Editor: Richard K. Assoian

The nonreceptor isoform of tyrosine phosphatase epsilon (cyt-PTPe) supports osteoclast adhesion and activity in vivo, leading to increased bone mass in female mice lacking PTPe (EKO mice). The structure and organization of the podosomal adhesion structures of EKO osteoclasts are abnormal; the molecular mechanism behind this is unknown. We show here that EKO podosomes are disorganized, unusually stable, and reorganize poorly in response to physical contact. Phosphorylation and activities of Src, Pyk2, and Rac are decreased and Rho activity is increased in EKO osteoclasts, suggesting that integrin signaling is defective in these cells. Integrin activation regulates cyt-PTPe by inducing Src-dependent phosphorylation of cyt-PTPe at Y638. This phosphorylation event is crucial because wild-type—but not Y638F—cyt-PTPe binds and further activates Src and restores normal stability to podosomes in EKO osteoclasts. Increasing Src activity or inhibiting Rho or its downstream effector Rho kinase in EKO osteoclasts rescues their podosomal stability phenotype, indicating that cyt-PTPe affects podosome stability by functioning upstream of these molecules. We conclude that cyt-PTPe participates in a feedback loop that ensures proper Src activation downstream of integrins, thus linking integrin signaling with Src activation and accurate organization and stability of podosomes in osteoclasts.

Present address: Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065.

Address correspondence to: Ari Elson (ari.elson{at}weizmann.ac.il).

Abbreviations used: cyt-PTPe, nonreceptor isoform of PTPe; EKO, PTPe-deficient; M-CSF, macrophage colony-stimulating factor; OCL, osteoclast-like cell; PTP, protein tyrosine phosphatase; RANKL, receptor activator of nuclear factor-B; RPTPe, receptor-type isoform of PTPe; SZL, sealing zone-like structure; WT, wild type.