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J. Biol. Chem., Vol. 278, Issue 43, 41921-41929, October 24, 2003

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Osteopontin Regulation by Inorganic Phosphate Is ERK1/2-, Protein Kinase C-, and Proteasome-dependent^*

George R. Beck, Jr. and Nicole Knecht

From the National Cancer Institute-Frederick, Center for Cancer Research, Basic Research Laboratory, Frederick, Maryland 21702

The generation of inorganic phosphate by alkaline phosphatase during osteoblast differentiation represents an important signaling event, although the molecular and cellular consequences are currently undefined. We have previously described osteopontin as a gene regulated by an increase in inorganic phosphate not only in osteoblasts but also in other cell types. We describe here the identification of specific signaling pathways required for the stimulation of osteopontin expression by inorganic phosphate. We have determined that phosphate selectively activates the extracellular signal-regulated kinase (ERK1/2) signaling pathway but does not activate the other mitogen-activated protein kinase signaling proteins, p38, or the c-Jun N-terminal kinase. In addition, our results suggest that cellular exposure to 10 mM inorganic phosphate causes a biphasic ERK1/2 activation. The second ERK1/2 activation is required for osteopontin regulation, whereas the first is not sufficient. Analysis of common protein kinase families has revealed that phosphate-induced osteopontin expression specifically uses a protein kinase C-dependent signaling pathway. In addition, our results suggest that protein kinase C and ERK1/2 are not part of the same pathway but constitute two distinct pathways. Finally, we have determined that the proteasomal activity is required not only for phosphate-induced expression of osteopontin but also for the induction of osteopontin in response to 12-O-tetradecanoylphorbol 13-acetate and okadaic acid. The data presented here define for the first time the ability of increased inorganic phosphate to stimulate specific signaling pathways resulting in functionally significant changes in gene expression and identify three important signaling pathways in the regulation of osteopontin.

Received for publication, April 29, 2003 , and in revised form, July 7, 2003.

^* This work was supported by grant CA84573 from the NCI, National Institutes of Health. 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: National Cancer Institute-Frederick, Center for Cancer Research, Basic Research Laboratory, Bldg. 576, Rm. 110, Frederick, MD 21702. Tel.: 301-846-1651; Fax: 301-846-6907; E-mail: gbeck{at}ncifcrf.gov.

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