Tripathi et al. describe how the kinase CDK5 promotes the activity and correct localization of the tumor suppressor DLC1.

DLC1 is down-regulated in a wide variety of tumors. The protein localizes to focal adhesions and contains a C-terminal GAP domain that inactivates Rho GTPases. How DLC1’s localization and activity are regulated is unknown, however.

Tripathi et al. discovered that CDK5 phosphorylates four serine residues in the N-terminal half of DLC1. Mutating these serines to nonphosphorylatable alanine residues inhibited DLC1’s ability to inactivate Rho and prevented the tumor suppressor’s localization to focal adhesions by inhibiting its interactions with the adhesion proteins talin and tensin.

CDK5 phosphorylation disrupted an interaction between DLC1’s N-terminal and GAP domains, suggesting that the kinase activates DLC1 by inducing its transition from a closed to an open conformation. Blocking this activation step reduced DLC1’s tumor suppressor functions; unlike the wild-type protein, nonphosphorylatable DLC1 was unable to suppress cell migration or inhibit the growth of tumors in vivo.

Although CDK5 suppresses tumor migration and growth by activating DLC1, the kinase itself can also promote the growth of some human tumors, presumably by phosphorylating other target proteins. Tripathi et al. found that poorly differentiated lung tumors often showed high CDK5 and low DLC1 expression, which might allow CDK5’s pro-oncogenic activities to predominate. Indeed, lung cancer cells lacking DLC1 grew in a CDK5-dependent manner, whereas cells expressing DLC1 grew independently of the kinase. Senior author Doug Lowy now plans to investigate other kinases that appear to oppose CDK5 and inactivate DLC1.

References

References
Tripathi
,
B.K.
, et al
.
2014
.
J. Cell Biol.
.

Author notes

Text by Ben Short