Dematin interacts with the Rasâguanine nucleotide exchange factor RasâGRF2 and modulates mitogenâactivated protein kinase pathways
2002
Lutchman, Mohini | Kim, Anthony C. | Cheng, Li | Whitehead, Ian P. | Oh, S Steven | Hanspal, Manjit | Boukharov, Andrey A. | Hanada, Toshihiko | Chishti, Athar H.
Erythroid dematin is a major component of red blood cell junctional complexes that link the spectrin–actin cytoskeleton to the overlying plasma membrane. Transcripts of dematin are widely distributed including human brain, heart, lung, skeletal muscle, and kidney. In vitro, dematin binds and bundles actin filaments in a phosphorylationâdependent manner. The primary structure of dematin consists of a Câterminal domain homologous to the ‘headpiece’ domain of villin, an actinâbinding protein of the brush border cytoskeleton. Except filamentous actin, no other binding partners of dematin have been identified. To investigate the physiological function of dematin, we employed the yeast twoâhybrid assay to identify dematinâinteracting proteins in the adult human brain. Here, we show that dematin interacts with the guanine nucleotide exchange factor RasâGRF2 by yeast twoâhybrid assay, and this interaction is further confirmed by blot overlay, surface plasmon resonance, coâtransfection, and coâimmunoprecipitation assays. Human RasâGRF2 is expressed in a variety of tissues and, similar to other guanine nucleotide exchange factors (GEFs), displays anchorage independent growth in soft agar. Coâtransfection and immunoblotting experiments revealed that dematin blocks transcriptional activation of Jun by RasâGRF2 and activates ERK1 via a RasâGRF2 independent pathway. Because much of the present evidence has centered on the identification of the Rho family of GTPases as key regulators of the actin cytoskeleton, the direct association between dematin and RasâGRF2 may provide an alternate mechanism for regulating the activation of Rac and Ras GTPases via the actin cytoskeleton.
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