title: ADAM10 promotes pituitary adenoma cell migration by regulating cleavage of CD44 and L1.
abstract: ADAM10 is a metalloproteinase that regulates invasiveness in many tumors. Here, we found that ADAM10 expression correlates with the invasiveness of pituitary adenomas and contributes to invasion by cleaving L1 and CD44. In high-grade pituitary adenoma patients, ADAM10 expression levels were found to be elevated compared with low-grade pituitary adenomas. In a phorbol 12-myristate 13-acetate (PMA)-stimulated pituitary adenoma cell line, AtT-20 cells, we found that the cleavage of L1 was correspondingly enhanced with the increased interaction between Src and Shc. Increases in PMA-induced L1 cleavage and the phosphorylation of residue 418 of Src (418Src) were promoted by overexpression of ADAM10. Inversely, knockdown of Adam10 suppressed PMA-induced L1 cleavage and the phosphorylation of Src, which was blocked by the Src inhibitor PP2 and the MEK inhibitor PD98059. On the other hand, calcium flux activation in AtT-20 cells resulted in increased CD44 cleavage, with reduction of the interaction between calmodulin and ADAM10. The induction of enhanced CD44 cleavage by calcium flux activation was inhibited by knockdown of Adam10. In addition, Adam10 knockdown repressed AtT-20 cell migration, which was reversed by CD44EXT (CD44 ectodomain cleavage). Collectively, these data indicated that ADAM10 facilitated cell migration through modulation of CD44 and L1 cleavage.
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Pan
authors.forename: Chong
authors.initials: C
authors.lastname: Han
authors.forename: Chunlin
authors.initials: C
authors.lastname: Wang
authors.forename: Guohan
authors.initials: G
authors.lastname: Hu
authors.forename: Chun
authors.initials: C
authors.lastname: Luo
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Gan
authors.forename: Fenglin
authors.initials: F
authors.lastname: Zhang
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Lu
authors.forename: Xuehua
authors.initials: X
authors.lastname: Ding
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D060787:Neoplasm Grading; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002147:Calmodulin; D018960:Hyaluronan Receptors; D039841:Leukocyte L1 Antigen Complex; D008565:Membrane Proteins; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D002118:Calcium