FAK and paxillin, two potential targets in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer in large part due to late diagnosis and a lack of effective screening tests. In spite of recent progress in imaging, surgery and new therapeutic options for pancreatic cancer, the overall five-year survival still remains unacceptably low. Numerous studies have shown that focal adhesion kinase (FAK) is activated in many cancers including PDAC and promotes cancer progression and metastasis. Paxillin, an intracellular adaptor protein that plays a key role in cytoskeletal organization, connects integrins to FAK and plays a key role in assembly and disassembly of focal adhesions. Here, we have reviewed evidence in support of FAK as a potential therapeutic target and summarized related combinatorial therapies.

Keywords: FAK; P53; integrins; pancreatic cancer; paxillin.

Figure 1. FAK plays a significant role in multiple signaling pathways that contribute to pancreatic cancer growth and metastasis

Several receptor systems induce FAK activation that then contributes to the unique function. For instance, RTK signaling through FAK contribute to pancreatic tumor growth and metastasis; however VEGFR mediated signaling through FAK triggers angiogenesis. In addition, K-RAS, which is frequently mutated in pancreatic cancer, is also linked to FAK. FAK also influences lamellipodia formation through activation of small GTPases and promotes homotypic cell adhesion indirectly through paxillin. Suppression of p53 expression by nuclear FAK may also indirectly contribute to tumor growth by inhibiting apoptosis. It is therefore very likely that there is subtle compartmentalization of FAK in the cell and the final effector function could be the result of a combination of FAK mediated and non-FAK mediated signals.

Figure 2. FAK and its potential interacting partners

In cancers, highly active receptor tyrosine kinases such as MET and EGFR phosphorylate Src that then interacts with FAK Y397 through SH2 domain. Juxtaposed Src phosphorylates FAK at Y576 and Y577 and possibly other sites, resulting in a highly active FAK both in terms of the kinase activity and as an adapter protein. In addition, it is also connected to RAS through GRB2 and SOS that feeds into MAPK pathway. The CT FAT domain interacts with paxillin that binds to the relatively short cytoplasmic tails of integrins. Although the FERM domain is capable of interacting with integrins and RTKs, the more favored interaction appears to be through paxillin anchored to focal adhesions.

Figure 3. Cell signaling pathways in which FAK plays a key role in tumorigenesis

FAK plays a central role in both Integrin and RTK mediated signaling and plays a key role in cytoskeletal changes, lamellipodia formation and cell proliferation and motility. Interaction of integrins with ECM also triggers downstream activation of FAK resulting in its autophosphorylation at Y397. In parallel, the RTK mediated activation of c-Src and its related kinases such as Fyn and Lck, results in the generation of an open SH2 domain that docks on to Y397 and further propagation of the signals. Src mediated Y925 phosphorylation recruits GRB2 which then leads to the activation of RAS and subsequently ERK2. The Y925 site in FAK is a part of paxillin interaction site and its phosphorylation is likely to disrupt FAK localization to focal adhesions. Interestingly, ERK2 mediated FAK phosphorylation at S910 also destabilizes paxillin-FAK interaction. Moreover, ERK2 mediated phosphorylation of paxillin can positively influence FAK adherence to focal adhesions. FAK thus promote cell proliferation and motility that ultimately translates to cancer metastasis. In addition, FAK has the potential to interact with p53 promoter site and down regulate p53 transcription, thus promoting cell survival.