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The human CD99 protein is a 32-kDa glycosylated transmembrane protein that regulates various cellular responses, including cell adhesion and leukocyte extravasation. We previously reported that CD99 activation suppresses ␤1 integrin activity through dephosphorylation of focal adhesion kinase (FAK) at Y397. We explored a molecular mechanism underlying the suppression of ␤1 integrin activity by CD99 agonists and its relevance to tumor growth in vivo. CD99-Fc fusion proteins or a series of CD99-derived peptides suppressed ␤1 integrin activity by specifically interacting with three conserved motifs of the CD99 extracellular domain. CD99CRIII3, a representative CD99-derived 3-mer peptide, facilitated protein kinase A-SHP2 interaction and subsequent activation of the HRAS/RAF1/MEK/ERK signaling pathway. Subsequently, CD99CRIII3 induced FAK phosphorylation at S910, which led to the recruitment of PTPN12 and PIN1 to FAK, followed by FAK dephosphorylation at Y397. Taken together, these results indicate that CD99-derived agonist ligands inhibit fibronectin-mediated ␤1 integrin activation through the SHP2/ERK/PTPN12/FAK signaling pathway.

Aim: Since DNA damage-related apoptosis is raising concerns regarding abnormal spermatogenesis, we investigated the changes in γ-H2AX during testicular germ cell apoptotic responses in the varicocele model. Materials and Methods: Varicocele was induced by partial ligation of the left renal vein and animals were sacrificed at 1, 3, and 4 weeks after varicocele creation. The levels of activated p53 and γ-H2AX formation were determined by Western blot analysis and immunohistochemistry. Results: γ-H2AX formation was augmented after varicocele creation, while a significant increase in p53 phosphorylation was detected in a time course-dependent manner. Varicocele-dependent nuclear γ-H2AX staining in the primary spermatocytes was prominent as degenerative foci, while little differences could be detected in spermatogonia. Conclusions: These results show that experimental varicocele may induce p53-dependent apoptosis through activation of γ-H2AX in the primary spermatocytes, and suggest that γ-H2AX may be related to apoptotic signal transduction in experimental varicocele.

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