Serum-induced Phosphorylation of the Serum Response Factor Coactivator MKL1 by the Extracellular Signal-regulated Kinase 1/2 Pathway Inhibits Its Nuclear Localization

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2008 Aug 13

PMID 18694962

Citations 68

Authors

Susanne Muehlich

Ruigong Wang

Seung-Min Lee

Thera C Lewis

Chao Dai

Ron Prywes

Affiliations

Soon will be listed here.

Abstract

Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related coactivator of the serum response factor (SRF) transcription factor, which has an integral role in differentiation, migration, and proliferation. Serum induces RhoA-dependent translocation of MKL1 from the cytoplasm to the nucleus and also causes a rapid increase in MKL1 phosphorylation. We have mapped a serum-inducible phosphorylation site and found, surprisingly, that its mutation causes constitutive localization to the nucleus, suggesting that phosphorylation of MKL1 inhibits its serum-induced nuclear localization. The key site, serine 454, resembles a mitogen-activated protein kinase phosphorylation site, and its modification was blocked by the MEK1 inhibitor U0126, implying that extracellular signal-regulated kinase 1/2 (ERK1/2) is the serum-inducible kinase that phosphorylates MKL1. Previous results indicated that G-actin binding to MKL1 promotes its nuclear export, and we found that MKL1 phosphorylation is required for its binding to actin, explaining its effect on localization. We propose a model in which serum induction initially stimulates MKL1 nuclear localization due to a decrease in G-actin levels, but MKL1 is then downregulated by nuclear export due to ERK1/2 phosphorylation.

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References

Zinck R, Hipskind R, Pingoud V, Nordheim A . c-fos transcriptional activation and repression correlate temporally with the phosphorylation status of TCF. EMBO J. 1993; 12(6):2377-87. PMC: 413468. DOI: 10.1002/j.1460-2075.1993.tb05892.x. View

Ridley A, Hall A . The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992; 70(3):389-99. DOI: 10.1016/0092-8674(92)90163-7. View

Du K, Chen M, Li J, Lepore J, Mericko P, Parmacek M . Megakaryoblastic leukemia factor-1 transduces cytoskeletal signals and induces smooth muscle cell differentiation from undifferentiated embryonic stem cells. J Biol Chem. 2004; 279(17):17578-86. DOI: 10.1074/jbc.M400961200. View

la Cour T, Kiemer L, Molgaard A, Gupta R, Skriver K, Brunak S . Analysis and prediction of leucine-rich nuclear export signals. Protein Eng Des Sel. 2004; 17(6):527-36. DOI: 10.1093/protein/gzh062. View

Selvaraj A, Prywes R . Megakaryoblastic leukemia-1/2, a transcriptional co-activator of serum response factor, is required for skeletal myogenic differentiation. J Biol Chem. 2003; 278(43):41977-87. DOI: 10.1074/jbc.M305679200. View

Sasazuki T, Sawada T, Sakon S, Kitamura T, Kishi T, Okazaki T . Identification of a novel transcriptional activator, BSAC, by a functional cloning to inhibit tumor necrosis factor-induced cell death. J Biol Chem. 2002; 277(32):28853-60. DOI: 10.1074/jbc.M203190200. View

Wang Z, Wang D, Hockemeyer D, McAnally J, Nordheim A, Olson E . Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature. 2004; 428(6979):185-9. DOI: 10.1038/nature02382. View

Guettler S, Vartiainen M, Miralles F, Larijani B, Treisman R . RPEL motifs link the serum response factor cofactor MAL but not myocardin to Rho signaling via actin binding. Mol Cell Biol. 2007; 28(2):732-42. PMC: 2223415. DOI: 10.1128/MCB.01623-07. View

Selvaraj A, Prywes R . Expression profiling of serum inducible genes identifies a subset of SRF target genes that are MKL dependent. BMC Mol Biol. 2004; 5:13. PMC: 516031. DOI: 10.1186/1471-2199-5-13. View

10.

Shaw P, Saxton J . Ternary complex factors: prime nuclear targets for mitogen-activated protein kinases. Int J Biochem Cell Biol. 2003; 35(8):1210-26. DOI: 10.1016/s1357-2725(03)00031-1. View

11.

Murai K, Treisman R . Interaction of serum response factor (SRF) with the Elk-1 B box inhibits RhoA-actin signaling to SRF and potentiates transcriptional activation by Elk-1. Mol Cell Biol. 2002; 22(20):7083-92. PMC: 139817. DOI: 10.1128/MCB.22.20.7083-7092.2002. View

12.

Bogerd H, Fridell R, BENSON R, Hua J, Cullen B . Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in vivo randomization-selection assay. Mol Cell Biol. 1996; 16(8):4207-14. PMC: 231418. DOI: 10.1128/MCB.16.8.4207. View

13.

Treisman R . Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors. Cell. 1986; 46(4):567-74. DOI: 10.1016/0092-8674(86)90882-2. View

14.

Gineitis D, Treisman R . Differential usage of signal transduction pathways defines two types of serum response factor target gene. J Biol Chem. 2001; 276(27):24531-9. DOI: 10.1074/jbc.M102678200. View

15.

Johansen F, Prywes R . Serum response factor: transcriptional regulation of genes induced by growth factors and differentiation. Biochim Biophys Acta. 1995; 1242(1):1-10. DOI: 10.1016/0304-419x(94)00014-s. View

16.

Williams G, Lau L . Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses. Mol Cell Biol. 1993; 13(10):6124-36. PMC: 364672. DOI: 10.1128/mcb.13.10.6124-6136.1993. View

17.

Cen B, Selvaraj A, Burgess R, Hitzler J, Ma Z, Morris S . Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes. Mol Cell Biol. 2003; 23(18):6597-608. PMC: 193697. DOI: 10.1128/MCB.23.18.6597-6608.2003. View

18.

Ballestrem C, Wehrle-Haller B, Imhof B . Actin dynamics in living mammalian cells. J Cell Sci. 1998; 111 ( Pt 12):1649-58. DOI: 10.1242/jcs.111.12.1649. View

19.

Favata M, Horiuchi K, Manos E, Daulerio A, Stradley D, Feeser W . Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998; 273(29):18623-32. DOI: 10.1074/jbc.273.29.18623. View

20.

Wang D, Chang P, Wang Z, Sutherland L, Richardson J, Small E . Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell. 2001; 105(7):851-62. DOI: 10.1016/s0092-8674(01)00404-4. View