A complex between FAK, RACK1, and PDE4D5 controls spreading initiation and cancer cell polarity

Serrels, B., Sandilands, E., Serrels, A., Baillie, G. , Houslay, M. D., Brunton, V. G., Canel, M., Machesky, L. M. , Anderson, K. I. and Frame, M. C. (2010) A complex between FAK, RACK1, and PDE4D5 controls spreading initiation and cancer cell polarity. Current Biology, 20(12), pp. 1086-1092. (doi: 10.1016/j.cub.2010.04.042)

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Publisher's URL: http://dx.doi.org/10.1016/j.cub.2010.04.042


A fundamental question in cell biology concerns how cells respond to their environment by polarizing after sensing directional cues. This requires the differential localization of protein complexes in cells, and it is important to identify and understand how these complexes function. Here we describe a novel “direction-sensing” pathway that links the integrin effector focal adhesion kinase (FAK [1,2,3,4,5,6,7]), the molecular scaffold protein RACK1 [8,9,10], and activity of one of its client proteins, PDE4D5, a cAMP-degrading phosphodiesterase. The complex is recruited to nascent adhesions and promotes cell polarity. We identify FAK FERM domain residues whose mutation impairs RACK1 binding. When re-expressed in cancer cells in which endogenous fak is deleted by Cre-lox-mediated recombination, the RACK1-binding-impaired FAK mutant protein does not support formation of nascent actin adhesion structures as cells spread. These cancer cells, like FAK-deficient cells, cannot undergo directional responses, including wound-induced polarization or chemotactic invasion into three-dimensional matrix gels. We show that RACK1 serves as the molecular bridge linking FAK to the recruitment of PDE4D5. FAK/RACK1/PDE4D5 is a novel ‘direction-sensing’ complex that acts to recruit specific components of the cAMP second-messenger system to nascent integrin adhesions and to the leading edge of polarizing cells.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Machesky, Professor Laura and Houslay, Professor Miles and Baillie, Professor George and Anderson, Professor Kurt and Sandilands, Ms Emma and Canel, Dr Marta and Frame, Prof Margaret and Serrels, Mr Alan and Serrels, Dr Bryan
Authors: Serrels, B., Sandilands, E., Serrels, A., Baillie, G., Houslay, M. D., Brunton, V. G., Canel, M., Machesky, L. M., Anderson, K. I., and Frame, M. C.
Subjects:Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Current Biology
ISSN (Online):1879-0445
Published Online:20 May 2010
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765Institute of Neuroscience and Psychology