Cytoskeletal proteins regulate cell adhesion and motility, and some have even been shown to mediate cell survival. In the June issue of Cancer Cell, Rakesh Kumar and colleagues report the surprising finding that two cytoskeletal proteins, p21-activated kinase 1 (PAK1) and the dynein light chain 1 (DLC1), interact to promote the survival and tumorigenic potential of breast cancer cells.

Kumar and colleagues began their studies by looking for new substrates of PAKs. PAKs phosphorylate Rho GTPases to control cytoskeletal organization, and also phosphorylate and inactivate the pro-apoptotic protein BAD to promote survival. In a yeast two-hybrid screen of a mammary-gland cDNA library, they found that PAK1 interacts directly with, and also phosphorylates, DLC1 — a component of the dynein motor complex. DLC1 not only regulates the microtubule-dependent motor function of dynein, but has also been shown to bind and inhibit activity of the pro-apoptotic protein BimL.

So what happens when these two pro-survival signalling proteins get together? Kumar and colleagues expressed normal and mutant forms of the proteins in a breast cancer cell line, and showed that the interaction between PAK1 and DLC1 is required for cell-cycle progression and survival. Cells that overexpressed either PAK1 or DLC1 were able to undergo anchorage-independent growth, indicating a malignant phenotype, and also led to oestrogen-independent tumour growth when transplanted into nude mice, unlike control cells. A DLC mutant that lacked the PAK1 phosphorylation site did not show tumorigenic potential in mice. Therefore, PAK1 phosphorylation of DLC1 seems to be required for cell survival and tumour formation. Furthermore, DLC1 levels were increased in 90% of the human breast tumour samples that the authors analysed.

How does PAK1 activation of DLC1 inhibit apoptosis and promote tumorigenesis? The authors propose a model whereby DLC1 sequesters BimL to the microtubules. Following pro-apoptotic signals, DLC1–BimL dimers are released and are free to inhibit BCL2, leading to cell death. When cells are exposed to growth factors or other survival signals, PAK1 becomes activated, leading to phosphorylation of the DLC1 and of BimL. This prevents the ability of the DLC1–BimL dimer to interact with and inhibit BCL2, leading to cell survival. So, increased levels of either PAK1 or DLC1 could promote cell survival and tumorigenesis. Further experiments are required to support this model and to investigate the role of these proteins in other tumour types.