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MAL: an actin-regulated SRF transcriptional coactivator

Objective

MAL: an actin-regulated SRF transcriptional coactivator

Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology:
¿ Actin as a transcriptional regulator
¿ Actin as a signalling molecule
¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function

We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/molecular biology/structural biology

Call for proposal

ERC-2010-AdG_20100317
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

THE FRANCIS CRICK INSTITUTE LIMITED
Address
1 Midland Road
NW1 1AT London
United Kingdom
Activity type
Research Organisations
EU contribution
€ 1 889 995
Principal investigator
Richard Treisman (Dr.)
Administrative Contact
Stéphane Maikovsky (Mr.)

Beneficiaries (2)

THE FRANCIS CRICK INSTITUTE LIMITED
United Kingdom
EU contribution
€ 1 889 995
Address
1 Midland Road
NW1 1AT London
Activity type
Research Organisations
Principal investigator
Richard Treisman (Dr.)
Administrative Contact
Stéphane Maikovsky (Mr.)
CANCER RESEARCH UK LBG

Participation ended

United Kingdom
Address
St John Street 407 Angel Building
EC1V 4AD London
Activity type
Research Organisations
Administrative Contact
Holly Elphinstone (Ms.)