HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 276, Issue 36, 33608-33615, September 7, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/36/33608    most recent M102754200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brodt, P. Articles by Zhang, D. Search for Related Content PubMed PubMed Citation Articles by Brodt, P. Articles by Zhang, D. Social Bookmarking                      What's this?

Cooperative Regulation of the Invasive and Metastatic Phenotypes by Different Domains of the Type I Insulin-like Growth Factor Receptor  Subunit^*

Pnina Brodt^§¶, Lucia Fallavollita, Abdel-Majid Khatib, Amir A. Samani^§, and Donglei Zhang

From the Departments of  Surgery and ^§ Medicine, McGill University Health Center, Royal Victoria Hospital, 687 Pine Ave W., Montreal, Quebec H3A 1A1, Canada

The receptor for the type 1 insulin-like growth factor (IGF-I) regulates multiple cellular functions impacting on the metastatic phenotype of tumor cells, including cellular proliferation, anchorage-independent growth, survival, migration, synthesis of the 72-kDa type IV collagenase and invasion. We have used site-directed mutagenesis to generate domain-specific mutants of the receptor  subunit to analyze the role of specific tyrosines in the regulation of the invasive/metastatic phenotype. Poorly invasive M-27 carcinoma cells expressing low receptor numbers were transfected with a plasmid vector expressing IGF-I receptor cDNA in which single or multiple tyrosine codons in the kinase domain, namely Tyr-1131, Tyr-1135, and Tyr-1136 or the C-terminal tyrosines 1250 and 1251 were substituted with phenylalanine. Changes in the invasive and metastatic properties were analyzed relative to M-27 cells expressing the wild type receptor. We found that cells expressing the Y1131F,Y1135F,Y1136F or Y1135F receptor mutants lost all IGF-IR-dependent functions and their phenotypes were indistinguishable from, or suppressed relative to, the parent line. The Y1250F,Y1251F substitution abolished anchorage-independent growth, cell spreading, and the anti-apoptotic effect of IGF-I whereas all other IGF-IR-dependent phenotypes were either unperturbed (i.e. mitogenicity) or only partially reduced (migration and invasion). The results identify three types of receptor-dependent functions in this model: those dependent only on an intact kinase domain (DNA synthesis), those dependent equally on kinase domain and Tyr-1250/1251 signaling (e.g. apoptosis, soft agar cloning) and those dependent on kinase domain and enhanced through Tyr-1250/1251 signaling (migration, invasion). They suggest that signals derived from both regions of the receptor cooperate to enhance tumor metastasis.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				B. Cady Regional Lymph Node Metastases; a Singular Manifestation of the Process of Clinical Metastases in Cancer: Contemporary Animal Research and Clinical Reports Suggest Unifying Concepts Ann. Surg. Oncol., June 1, 2007; 14(6): 1790 - 1800. [Abstract] [Full Text] [PDF]

				A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights Endocr. Rev., February 1, 2007; 28(1): 20 - 47. [Abstract] [Full Text] [PDF]

				S.-H. Oh, O.-H. Lee, C. P. Schroeder, Y. W. Oh, S. Ke, H.-J. Cha, R.-W. Park, A. Onn, R. S. Herbst, C. Li, et al. Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition. Mol. Cancer Ther., November 1, 2006; 5(11): 2685 - 2695. [Abstract] [Full Text] [PDF]

				G. M. Risinger Jr., T. S. Hunt, D. L. Updike, E. C. Bullen, and E. W. Howard Matrix Metalloproteinase-2 Expression by Vascular Smooth Muscle Cells Is Mediated by Both Stimulatory and Inhibitory Signals in Response to Growth Factors J. Biol. Chem., September 8, 2006; 281(36): 25915 - 25925. [Abstract] [Full Text] [PDF]

				N. Wang, T. Thuraisingam, L. Fallavollita, A. Ding, D. Radzioch, and P. Brodt The Secretory Leukocyte Protease Inhibitor Is a Type 1 Insulin-Like Growth Factor Receptor-Regulated Protein that Protects against Liver Metastasis by Attenuating the Host Proinflammatory Response. Cancer Res., March 15, 2006; 66(6): 3062 - 3070. [Abstract] [Full Text] [PDF]

				G. Loughran, N. C. Healy, P. A. Kiely, M. Huigsloot, N. L. Kedersha, and R. O'Connor Mystique Is a New Insulin-like Growth Factor-I-regulated PDZ-LIM Domain Protein That Promotes Cell Attachment and Migration and Suppresses Anchorage-independent Growth Mol. Biol. Cell, April 1, 2005; 16(4): 1811 - 1822. [Abstract] [Full Text] [PDF]

				P. A. Kiely, M. Leahy, D. O'Gorman, and R. O'Connor RACK1-mediated Integration of Adhesion and Insulin-like Growth Factor I (IGF-I) Signaling and Cell Migration Are Defective in Cells Expressing an IGF-I Receptor Mutated at Tyrosines 1250 and 1251 J. Biol. Chem., March 4, 2005; 280(9): 7624 - 7633. [Abstract] [Full Text] [PDF]

				H E Jones, L Goddard, J M W Gee, S Hiscox, M Rubini, D Barrow, J M Knowlden, S Williams, A E Wakeling, and R I Nicholson Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells Endocr. Relat. Cancer, December 1, 2004; 11(4): 793 - 814. [Abstract] [Full Text] [PDF]

				A. A. Samani, E. Chevet, L. Fallavollita, J. Galipeau, and P. Brodt Loss of Tumorigenicity and Metastatic Potential in Carcinoma Cells Expressing the Extracellular Domain of the Type 1 Insulin-Like Growth Factor Receptor Cancer Res., May 15, 2004; 64(10): 3380 - 3385. [Abstract] [Full Text] [PDF]

				M. Leahy, A. Lyons, D. Krause, and R. O'Connor Impaired Shc, Ras, and MAPK Activation but Normal Akt Activation in FL5.12 Cells Expressing an Insulin-like Growth Factor I Receptor Mutated at Tyrosines 1250 and 1251 J. Biol. Chem., April 30, 2004; 279(18): 18306 - 18313. [Abstract] [Full Text] [PDF]

				G. Blum, A. Gazit, and A. Levitzki Development of New Insulin-like Growth Factor-1 Receptor Kinase Inhibitors Using Catechol Mimics J. Biol. Chem., October 17, 2003; 278(42): 40442 - 40454. [Abstract] [Full Text] [PDF]

				M. Suzuki, H. Kobayashi, Y. Tanaka, Y. Hirashima, N. Kanayama, Y. Takei, Y. Saga, M. Suzuki, H. Itoh, and T. Terao Bikunin Target Genes in Ovarian Cancer Cells Identified by Microarray Analysis J. Biol. Chem., April 18, 2003; 278(17): 14640 - 14646. [Abstract] [Full Text] [PDF]

				Y. Tang, D. Zhang, L. Fallavollita, and P. Brodt Vascular Endothelial Growth Factor C Expression and Lymph Node Metastasis Are Regulated by the Type I Insulin-like Growth Factor Receptor Cancer Res., March 15, 2003; 63(6): 1166 - 1171. [Abstract] [Full Text] [PDF]

				W.-H. Shen, J.-H. Zhou, S. R. Broussard, G. G. Freund, R. Dantzer, and K. W. Kelley Proinflammatory Cytokines Block Growth of Breast Cancer Cells by Impairing Signals from a Growth Factor Receptor Cancer Res., August 15, 2002; 62(16): 4746 - 4756. [Abstract] [Full Text] [PDF]

				P. A. Kiely, A. Sant, and R. O'Connor RACK1 Is an Insulin-like Growth Factor 1 (IGF-1) Receptor-interacting Protein That Can Regulate IGF-1-mediated Akt Activation and Protection from Cell Death J. Biol. Chem., June 14, 2002; 277(25): 22581 - 22589. [Abstract] [Full Text] [PDF]

				A.-M. Khatib, G. Siegfried, M. Chretien, P. Metrakos, and N. G. Seidah Proprotein Convertases in Tumor Progression and Malignancy : Novel Targets in Cancer Therapy Am. J. Pathol., June 1, 2002; 160(6): 1921 - 1935. [Abstract] [Full Text] [PDF]