Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma

Abstract

~p l f 5~"~, a protein tyrosine kinase (PTK) co-localized with integrtns in focal adhesion plaques, is known to transduce signals invoked in the regulation of cell adhesion and motility as well as the anchorage-independent growth of transformed cells. We investigated whether pp I 25F*K could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up-regulation of pp I 25F*K expression, its activation by phosphoryiation on tyrosine and its association with paxillin and p 5 W were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp12SFAK signalling complexes. The increase in expression and activation of pp I 25FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of ~p l 2 5~~and FAK mRNA were observed in highly tumorigenic PC-3 cells as was the presence of activated p~1 2 5 "~, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, ~~1 2 5~~ formed signalling complexes with both paxillin and p5Wk in PC-3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp 125FM activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.8 1996 Wiley-Liss, Inc.The processes of tumour formation, invasion and metastasis represent complex genetic and epigenetic events that lead to cell transformation, with subsequent changes in adhesive properties that allow the transformed cells to migrate, gain access to the circulation and form metastatic colonies (Liottaet al., 1991). It is likely that some changes in adhesion occur at focal adhesion plaques which are cell/extracellular matrix (ECM) contact points containing integrin receptors, cytoskeletal components and intracellular signalling proteins such as focal adhesion kinase ( p~1 2 5~"~) , a non-receptor protein tyrosine kinase (PTK) (Clark and Brugge, 1995; Schaller et al., 1992). Evidence from several laboratories has shown that cell adhesion to the ECM through the integrin receptors leads to an increase in the tyrosine phosphorylation of pp12FAK and a subsequent stimulation of its activity (Juliano and Haskill, 1993). Phosphorylation of ~~1 2 . 5~~ is also increased in Rous sarcoma virus-transformed cells, as a result of the expression of ~p 6 0 ' ' -~~~ oncogene product, which is also a PTK (Guan and Shalloway, 1992). These changes lead to the disassembly of actin filaments and focal adhesions and, consequently, to a decrease in cell adhesion and an increase in anchorageindependent growth.As part of the integrin signalling pathway, ~~1 2 5~"~ has also been shown to be associated with various intracellular proteins in fibroblasts and transformed cells . Among them, paxillin, a cytoskeletal phosphotyrosine (pY)-containing protein invol...

ErbB-2 via PYK2 upregulates the adhesive ability of androgen receptor-positive human prostate cancer cells

“…Despite that further study is required, these results suggest an important role of AR in regulating PYK2 expression in PCa cells. Additionally, LNCaP cells express an inactive form of FAK (Tremblay et al, 1996). PYK2-mediated functions are carried out by activating multiple downstream signaling molecules, including ERK/ MAPK (Lev et al, 1995), p38/MAPK (Pandey et al, 1999), c-Src (Dikic et al, 1996) and paxillin (Li and Earp, 1997), which lead to the differential regulation of cell adhesion in different cell types.…”

FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

“…Furthermore, the prognosis of patients who overexpressed FAK was significantly less favourable than that of FAK-overexpression (À) patients. A number of reports have indicated that FAK may be up-regulated in human tumour cells of diverse origin (Weiner et al, 1993;Akasaka et al, 1995;Owens et al, 1995;Tremblay et al, 1996;McCormack et al, 1997;Cance et al, 2000). In some of these reports, there has been a suspected relationship between FAK expression and metastatic ability (Owens et al, 1995;Tremblay et al, 1996).…”

“…Cells derived from pp125 FAK À/À mouse embryos exhibit reduced migration as a result of impaired adhesion turnover (Ilic et al, 1995(Ilic et al, , 1996. Overexpression of FAK has been reported in a number of invasive human cancer cells (Weiner et al, 1993;Akasaka et al, 1995;Owens et al, 1995;Tremblay et al, 1996;McCormack et al, 1997;Cance et al, 2000). In some of these reports, there is a suspected relationship between FAK expression and metastatic ability.…”

Tpl2 induces castration resistant prostate cancer progression and metastasis

“…The activation of FAK and Akt has been reported to be closely associated with cell proliferation, anoikis resistance, migration, invasion and stemness of PC cells. [27][28][29][30][31][40][41][42] CXCR4 leads to the activation of diverse intracellular signaling pathways including the Akt pathway, 34,43,44 and CXCL12 evoked increased expression of FAK and enhanced FAK phosphorylation. 35 Furthermore, it has been established that the tumorigenic and metastatic process of PC is regulated by CXCL12/CXCR4 axis.…”