FAK, Pyk2, and p190RhoGEF in Cell Motility

Focal adhesion kinase is an important signaling molecule in integrin-mediated cell signaling and cell adhesion. In FAK genetic knockout (FAK-null) cells, its closely homologous relative proline-rich kinase (Pyk2) is upregulated in FAK-null fibroblasts to partially compensate, but the mechanisms of Pyk2 upregulation and compensation remain undefined¹. A recent study by Yangmi Lim, David Schlaepfer, and colleagues takes a step towards elucidating the latter, by demonstrating both FAK and Pyk2 signaling through a RhoA guanine nucleotide exchange factor (GEF)².

First, FAK-null cells still retain the capacity to form focal adhesions and phosphorylate paxillin. Pyk2 knockdown (with shRNA) in FAK-null cells almost abolished both capacities however. Similarly, the Pyk2 knockdown reduced proliferation FAK-null fibroblasts, as well as blocking motility altogether and generating tail-retraction motility defects. Pretty basic finding there.

Second, and more importantly, Lim and colleagues identified RhoA activation and promotion of p190RhoGEF expression by Pyk2 in a series of immunoblots, providing a mechanism for compensation by Pyk2 in FAK-null fibroblasts. And the way that Pyk2 effects motility through p190RhoGEF is really interesting, as shown by three sorts of evidence: p190RhoGEF knockdown in FAK-null and normal cells (i) restores normal fibroblast morphology (see image); (ii) decreases formation of focal adhesions; (iii) and inhibits motility. Intuitively, it seems strange to me that p190RhoGEF knockdown would result in both (i) and (ii/iii), but then again, the GTP/GDP exchange cycle of RhoA does have significant impacts on the cell if out of balance. Here, RhoGEF activity effectively makes RhoA constitutively active, in a trade-off between morphology and motility phenotypes - FAK, but not Pyk2, is able to regulate RhoA at *just* the right levels, probably through Src signaling through p190RhoGAP.

So, what about Rac regulation by Pyk2?

Just Science

1. Sieg DJ, et al. (1998) EMBO J., 17 : 5933 – 5947. doi:10.1093/emboj/17.20.5933
2. Lim Y, et al. (2008) J Cell Biol. 180:187–203. doi:10.1083/jcb.200708194
3. Leslie M (2008) J Cell Biol. 180:2. doi:10.1083/jcb.1801iti2

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