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Molecular and Cellular Biology, August 2009, p. 4177-4187, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00035-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Serine Protease HtrA1 Associates with Microtubules and Inhibits Cell Migration{triangledown}

Jeremy Chien,1 Takayo Ota,1 Giovanni Aletti,1 Ravi Shridhar,2 Mariarosaria Boccellino,3 Lucio Quagliuolo,3 Alfonso Baldi,3 and Viji Shridhar1*

Department of Laboratory Medicine and Pathology, Mayo Clinic Cancer Center, Rochester, Minnesota 55905,1 Barbara Ann Karmanos Cancer Institute, Gershenson Radiation Oncology Center, Detroit, Michigan 48201,2 Department of Biochemistry, Second University of Naples, 80138 Naples, Italy3

Received 9 January 2009/ Returned for modification 25 February 2009/ Accepted 18 May 2009

HtrA1 belongs to a family of serine proteases found in organisms ranging from bacteria to humans. Bacterial HtrA1 (DegP) is a heat shock-induced protein that behaves as a chaperone at low temperature and as a protease at high temperature to help remove unfolded proteins during heat shock. In contrast to bacterial HtrA1, little is known about the function of human HtrA1. Here, we report the first evidence that human HtrA1 is a microtubule-associated protein and modulates microtubule stability and cell motility. Intracellular HtrA1 is localized to microtubules in a PDZ (PSD95, Dlg, ZO1) domain-dependent, nocodazole-sensitive manner. During microtubule assembly, intracellular HtrA associates with centrosomes and newly polymerized microtubules. In vitro, purified HtrA1 promotes microtubule assembly. Moreover, HtrA1 cosediments and copurifies with microtubules. Purified HtrA1 associates with purified {alpha}- and β-tubulins, and immunoprecipitation of endogenous HtrA1 results in coprecipitation of {alpha}-, β-, and {gamma}-tubulins. Finally, downregulation of HtrA1 promotes cell motility, whereas enhanced expression of HtrA1 attenuates cell motility. These results offer an original identification of HtrA1 as a microtubule-associated protein and provide initial mechanistic insights into the role of HtrA1 in theregulation of cell motility by modulating microtubule stability.

* Corresponding author. Mailing address: Experimental Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. Phone: (507) 266-2775. Fax: (507) 284-1678. E-mail: shridhar.vijayalakshmi{at}mayo.edu

{triangledown} Published ahead of print on 26 May 2009.

Molecular and Cellular Biology, August 2009, p. 4177-4187, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00035-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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