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MBC in Press, published online ahead of print April 30, 2008
Mol. Biol. Cell 10.1091/mbc.E07-10-1094

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Submitted on October 31, 2007
Revised on April 15, 2008
Accepted on April 22, 2008

A Raft-derived, Pak1-regulated Entry Participates in {alpha}2{beta}1 Integrin-dependent Sorting to Caveosomes

Mikko Karjalainen,*{dagger} Elina Kakkonen,*{dagger} Paula Upla,* Heli Paloranta,* Pasi Kankaanpää,{ddagger} Prisca Liberali,{sect} G. Herma Renkema,|| Timo Hyypiä,¶ Jyrki Heino,{ddagger} and Varpu Marjomäki*

*Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, FI-40351 Jyväskylä, Finland; {ddagger}Department of Biochemistry, University of Turku, FI-20014 Turku, Finland; {sect}Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy; ||Institute of Medical Technology, University of Tampere and Tampere University Hospital, FI-22014 Tampere, Finland; Department of Virology, University of Turku, FI-20520 Turku, Finland

Monitoring Editor: Jean Gruenberg

We have previously shown that a human picornavirus echovirus 1 (EV1) is transported to caveosomes during 2 h together with its receptor {alpha}2{beta}1 integrin. Here we show that the majority of early uptake does not occur through caveolae. {alpha}2{beta}1 integrin, clustered by antibodies or by EV1 binding, is initially internalized from lipid rafts into tubulo-vesicular structures. These vesicles accumulate fluid-phase markers but do not initially colocalize with caveolin-1 or internalized SV40 (SV40). Furthermore, the internalized endosomes do not contain GPI-anchored proteins or flotillin 1 suggesting that clustered {alpha}2{beta}1 integrin does not enter the GEEC (GPI-anchored protein enriched endosomal compartment) or flotillin pathways, respectively. Endosomes mature further into larger multivesicular bodies between 15 min to 2 h and concomitantly recruit caveolin-1 or SV40 inside. Cell entry is regulated by Pak1, Rac1, PI3 kinase, PLC, and actin but not by dynamin 2 in SAOS-{alpha}2{beta}1 cells. An amiloride analog, EIPA, blocks infection, causes integrin accumulation in early tubulovesicular structures and prevents their structural maturation into multivesicular structures. Our results altogether suggest that {alpha}2{beta}1 integrin clustering defines its own entry pathway which is Pak1 dependent but clathrin and caveolin independent and which is able to sort cargo to caveosomes.

{dagger}These authors contributed equally to this work.

Address correspondence to: Varpu Marjomäki (vmarjoma{at}cc.jyu.fi)






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