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Molecular and Cellular Biology, March 2006, p. 1932-1947, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1932-1947.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Adaptor Protein Tom1L1 Is a Negative Regulator of Src Mitogenic Signaling Induced by Growth Factors

Mélanie Franco,1 Olivia Furstoss,1,{dagger} Valérie Simon,1 Chrsitine Benistant,1 Wan Jing Hong,2 and Serge Roche1*

CRBM, CNRS FRE2593, 1919 Route de Mende, 34293 Montpellier, France,1 Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore2

Received 28 July 2005/ Returned for modification 8 September 2005/ Accepted 14 November 2005

The Src family of protein-tyrosine kinases (SFK) play important roles in mitogenesis and morphological changes induced by growth factors. The involved substrates are, however, ill defined. Using an antiphosphotyrosine antibody to screen tyrosine-phosphorylated cDNA expression library, we have identified Tom1L1, an adaptor protein of the Tom1 family and a novel substrate and activator of the SFK. Surprisingly, we found that Tom1L1 does not promote DNA synthesis induced by Src. Furthermore, we report that Tom1L1 negatively regulates SFK mitogenic signaling induced by platelet-derived growth factor (PDGF) through modulation of SFK-receptor association: (i) Tom1L1 inhibits DNA synthesis induced by PDGF; (ii) inhibition is overcome by c-myc expression or p53 inactivation, two regulators of SFK mitogenic function; (iii) Src or Fyn coexpression overrides Tom1L1 mitogenic activity; (iv) overexpression of the adaptor reduces Src association with the receptor; and (v) protein inactivation potentiates receptor complex formation, allowing increased SFK activation and DNA synthesis. However, Tom1L1 affects neither DNA synthesis induced by the constitutively active allele SrcY527F nor SFK-regulated actin assembly induced by PDGF. Finally, overexpressed Tom1 and Tom1L2 also associate with Src and affected mitogenic signaling in agreement with some redundancy among members of the Tom1 family. We concluded that Tom1L1 defines a novel mechanism for regulation of SFK mitogenic signaling induced by growth factors.

* Corresponding author. Mailing address: CRBM, CNRS FRE2593, 1919 Route de Mende, 34293 Montpellier Cedex 05, France. Phone: 33 467 61 33 73. Fax: 33 467 52 15 59. E-mail: Serge.Roche{at}crbm.cnrs.fr.

{dagger} Present address: Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada.

Molecular and Cellular Biology, March 2006, p. 1932-1947, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1932-1947.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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