The process of metastasis requires migration of tumor cells from the primary tumor into the vasculature and the target tissue. 1 Studies with a variety of tumor types have shown that metastatic tumor cells are more highly motile than are nonmetastatic cells. [2][3][4][5] Cellular migration is influenced by the degree of adhesiveness to a substratum, signaling through integrins, and active turnover of focal adhesions. 6,7 There is, however, a fine balance between adherence/detachment and motility. A strong shift toward focal adhesion formation results in strong adherence with little migration, whereas excessive loss of adherence results in the inability to navigate across the substratum. Interactions with a substratum leads to the formation and stabilization of focal adhesions, where the actin skeleton converges with integrins and an interconnection of protein complexes. 6,8 Among the focal adhesion proteins that mediates communication through integrins during interaction with the substratum is the cytosolic tyrosine kinase FAK. 6,9 When FAK activity is reduced, cellular adhesiveness is diminished 10. During motility, the levels of membrane-associated FAK decline. 11 In adherent cells, FAK is complexed with Src within stable focal adhesions. 6 The tyrosine kinase Src (pp60c-Src) is a prototype of a family of tyrosine kinases that also includes Fyn, Lyn, Yes. Src Y527 residue (Y530 in humans) regulates Src activity. 7,12 When phosphorylated, Y527 inactivates Src by undergoing a conformational change and binding with the Src SH2 domain. FAK complexing with Src is important in Src activation and stabilization of focal adhesions, Src activation can also increase turnover of focal adhesions and increase motility. [13][14][15] An in vivo role of FAK or Src in cancer invasion has been suggested by their increased levels in malignancies. 16 Key in the formation of stable adhesions is association of FAK and Src with paxillin. Paxillin is a 68 kDa adaptor protein that binds a multitude of structural and signaling molecules within focal adhesions. The ability of paxillin to facilitate interaction between molecules of the focal adhesions is regulated by its level of serine and tyrosine phosphorylation. 17 Focal adhesion formation and cellular adhesion are accompanied by tyrosine phosphorylation of paxillin, 18,19 whereas the breakdown of focal adhesions and loss of adherence are accompanied by tyrosine dephosphorylation of paxillin. 20,21 Blocking tyrosine phosphorylation of paxillin results in failure to form organized stress fibers and focal adhesions, and defective cellular adherence. 22 In contrast, serine phosphorylation of paxillin has been associated with redistribution of paxillin from the tyrosine-phosphorylated focal adhesions and increased cell scattering. 23 Our studies with a murine Lewis lung carcinoma model have shown regulation of cell migration by the serine/threonine protein phosphatase PP-2A. 3,24 More highly motile and metastatic tumor cells have diminished PP-2A activity. Inhibition of PP-2A activity wit...
