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Molecular and Cellular Biology, July 2002, p. 4587-4597, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4587-4597.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cell Attachment to the Extracellular Matrix Induces Proteasomal Degradation of p21CIP1 via Cdc42/Rac1 Signaling

Wenjie Bao,1,2 Minna Thullberg,1 Hongquan Zhang,1 Anatoli Onischenko,1 and Staffan Strömblad1,2*

Karolinska Institutet, Department of Microbiology, Pathology and Immunology, Division of Pathology, Huddinge University Hospital, Stockholm,1 Södertörns Högskola, Huddinge, Sweden2

Received 7 February 2002/ Returned for modification 6 March 2002/ Accepted 3 April 2002

The cyclin-dependent kinase 2 (Cdk2) inhibitors p21CIP1 and p27KIP1 are negatively regulated by anchorage during cell proliferation, but it is unclear how integrin signaling may affect these Cdk2 inhibitors. Here, we demonstrate that integrin ligation led to rapid reduction of p21CIP1 and p27KIP1 protein levels in three distinct cell types upon attachment to various extracellular matrix (ECM) proteins, including fibronectin (FN), or to immobilized agonistic anti-integrin monoclonal antibodies. Cell attachment to FN did not rapidly influence p21CIP1 mRNA levels, while the protein stability of p21CIP1 was decreased. Importantly, the down-regulation of p21CIP1 and p27KIP1 was completely blocked by three distinct proteasome inhibitors, demonstrating that integrin ligation induced proteasomal degradation of these Cdk2 inhibitors. Interestingly, ECM-induced proteasomal proteolysis of a ubiquitination-deficient p21CIP1 mutant (p21K6R) also occurred, showing that the proteasomal degradation of p21CIP1 was ubiquitin independent. Concomitant with our finding that the small GTPases Cdc42 and Rac1 were activated by attachment to FN, constitutively active (ca) Cdc42 and ca Rac1 promoted down-regulation of p21CIP1. However, dominant negative (dn) Cdc42 and dn Rac1 mutants blocked the anchorage-induced degradation of p21CIP1, suggesting that an integrin-induced Cdc42/Rac1 signaling pathway activates proteasomal degradation of p21CIP1. Our results indicate that integrin-regulated proteasomal proteolysis might contribute to anchorage-dependent cell cycle control.

* Corresponding author. Mailing address: Karolinska Institutet, Department of Microbiology, Pathology and Immunology, Huddinge University Hospital, F46 SE-141 86 Stockholm, Sweden. Phone: 46-8-58581032. Fax: 46-8-58581020. E-mail: Staffan.Stromblad{at}impi.ki.se.

Molecular and Cellular Biology, July 2002, p. 4587-4597, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4587-4597.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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