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J. Biol. Chem., Vol. 279, Issue 40, 41377-41383, October 1, 2004

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Protein Phosphatase 2A, a Negative Regulator of the ERK Signaling Pathway, Is Activated by Tyrosine Phosphorylation of Putative HLA Class II-associated Protein I (PHAPI)/pp32 in Response to the Antiproliferative Lectin, Jacalin^*

Lu-Gang Yu, Len C. Packman¶, Mike Weldon¶, Jane Hamlett||, and Jonathan M. Rhodes

From the Departments of Medicine and ^||Human Anatomy and Cell Biology, University of Liverpool, Liverpool, L69 3GA and the ^¶Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, United Kingdom

Protein phosphatase 2A (PP2A) is a family of mammalian serine/threonine phosphatases that is involved in the control of many cellular functions including those mediated by extracellular signal-regulated kinase (ERK) signaling. While investigating the reversible antiproliferative effect of the dietary lectin, jacalin, which binds the Thomsen-Friedenreich antigen (galactose 1–3 N-acetylgalactosamine -), we have found that this lectin (30 µg/ml) induces rapid, transient, tyrosine phosphorylation of putative human HLA-DR-associated protein I (PHAPI, also known as the tumor suppressor pp32) in HT29 human colon cancer cells. This is accompanied by the release of PP2A from association with PHAPI, allowing increased phosphatase activity of PP2A (by 42 ± 10% at 10 min) and consequent complete dephosphorylation of the ERK kinase, MEK1/2, by 10 min and of ERK1/2 by 60 min. PHAPI knockdown by RNA interference abolished the effects of jacalin on PP2A activation and MEK inhibition. Thus phosphorylation of PHAPI/pp32 is a critical regulatory step in PP2A activation and ERK signaling.

Received for publication, January 5, 2004 , and in revised form, June 21, 2004.

^* This work was supported in part by grants from the World Cancer Research Fund (to L.-G. Y and J. M. R.), the North West Cancer Research Fund (to L.-G. Y. and J. M. R.), and by Medical Research Council Co-operative Grant GR990432 (to J. M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 44 151-794-6820; Fax: 44-151-794-6825; E-mail: lgyu{at}liv.ac.uk.

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