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Molecular and Cellular Biology, November 2004, p. 9390-9400, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9390-9400.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Central Role of the Threonine Residue within the p+1 Loop of Receptor Tyrosine Kinase in STAT3 Constitutive Phosphorylation in Metastatic Cancer Cells

Zheng-long Yuan,1,2,{dagger} Ying-jie Guan,1,2,{dagger} Lijuan Wang,1 Wenyi Wei,3,{ddagger} Agnes B. Kane,1 and Y. Eugene Chin1,2,3*

Departments of Pathology and Laboratory Medicine,1 Surgery Science,2 Molecular Biology, Cellular Biology, and Biochemistry, Brown University School of Medicine/Rhode Island Hospital, Providence, Rhode Island3

Received 2 February 2004/ Returned for modification 26 May 2004/ Accepted 2 August 2004

The receptor tyrosine kinases (RTKs) RET, MET, and RON all carry the Metp+1loop->Thr point mutation (i.e., 2B mutation), leading to the formation of tumors with high metastatic potential. Utilizing a novel antibody array, we identified constitutive phosphorylation of STAT3 in cells expressing the 2B mutation but not wild-type RET. MET or RON with the 2B mutation also constitutively phosphorylated STAT3. Members of the EPH, the only group of wild-type RTK that carry Thrp+1loop residue, are often expressed unexpectedly in different types of cancers. Ectopic expression of wild-type but not Thrp+1loop->Met substituted EPH family members constitutively phosphorylated STAT3. In both RTKMetp+1loop with 2B mutation and wild-type EPH members the Thrp+1loop residue is required for constitutive kinase autophosphorylation and STAT3 recruitment. In multiple endocrine neoplasia 2B (MEN-2B) patients expressing RETM918T, nuclear enrichment of STAT3 and elevated expression of CXCR4 was detected in metastatic thyroid C-cell carcinoma in the liver. In breast adenocarcinoma cell lines expressing multiple EPH members, STAT3 constitutively bound to the promoters of MUC1, MUC4, and MUC5B genes. Inhibiting STAT3 expression resulted in reduced expression of these metastasis-related genes and inhibited mobility. These findings provide insight into Thrp+1loop residue in RTK autophosphorylation and constitutive activation of STAT3 in metastatic cancer cells.

* Corresponding author. Mailing address: Department of Surgery Science, Brown University School of Medicine/Rhode Island Hospital, 593 Eddy St., Providence, RI 02903. Phone: (401) 444-0172. Fax: (401) 444-3278. E-mail: y_eugene_chin{at}brown.edu.

{dagger} Z.-L.Y. and Y.-J.G. contributed equally to this study.

{ddagger} Present address: Department of Medical Oncology, Dana-Farber Cancer Center, Boston, MA 02115.

Molecular and Cellular Biology, November 2004, p. 9390-9400, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9390-9400.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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