PHYSIOLOGICAL ROLES OF A KINASE-DEFECTIVE GROWTH FACTOR RECEPTORS

Research Project

Project/Area Number	10044289
Research Category	Grant-in-Aid for Scientific Research (C).
Allocation Type	Single-year Grants
Section	一般
Research Field	Hematology
Research Institution	Kobe University
Principal Investigator	MATSUI Toshimitsu KOBE UNIV HOSPITAL, LECTURER, 医学部・附属病院, 講師 (10219371)
Co-Investigator(Kenkyū-buntansha)	伊藤光宏ロックフェラー大学, 研究員中本賢ハーバート大学, 医学部, 研究員 BERGEMANN An マウントサイナイ医科大学, 病理学, 助教授 AARONSON Stu マウントサイナイ医科大学, 癌センター, 教授
Project Period (FY)	1998 – 1999
Project Status	Completed (Fiscal Year 1999)
Budget Amount *help	¥1,800,000 (Direct Cost: ¥1,800,000) Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000) Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywords	HEP / EphB6 / GROWTH FACTOR RECEPTOR / TYROSINE KINASE / T LYMPHOSYTE / EPHRIN B2 / THYMUS / KNOCKOUT MOUSE / Eph / 受容体 / ErbB3
Research Abstract	Receptor protein tyrosine kinases play key roles in cellular proliferation and differentiation in a wide variety of cell types. The genetic alteration of the receptor genes are involved in oncogenesis. The Eph-family receptors are the largest known family of receptor protein tyrosine kinases, and are expressed in the embryo and nervous system as well as in human malignancies of various tissues. There are rapidly accumulating evidences that they function in a variety of morphogenic events. The best known function of the ephrins and Eph-family receptors is their role in the control of axonal pathfinding and cell migration in the nervous system through repulsive interactions. They may also play roles in angiogenesis, tissue patterning and tumor formation. Eph receptor was initially identified as an orphan receptor expressed in human cancer, and transcripts of several Eph-family genes have been shown to be expressed in a variety of tumor cells. However, their specific functions in oncogene … More sis remain to be established. To understand the functional significance in human malignancies of Eph receptors, it is important to elucidate the expression patterns of these receptors in transformed cells as well as the expression patterns of their normal counterparts. In the present study, we examined the expression of the kinase-defective EphB6 receptor in normal blood cells and human hematopoietic malignancies to clarify whether EphB6 is differentially expressed between normal and transformed hematopoietic cells and to ascertain the specific roles of EphB6 in the hematopoietic system. Although most kinase-defective growth factor receptor proteins are associated with pathogenic conditions, a kinase-defective Eph-family receptor protein, EphB6, is expressed in normal human tissues. A very simple population of normal human peripheral white blood cells (0.57±0.07%, n=12) expressed EphB6. The EphB6-positive cells were CD2ィイD1+ィエD1, CD7ィイD1+ィエD1, CD3ィイD1+ィエD1 and CD4ィイD1+ィエD1 or CD8ィイD1+ィエD1 lymphocytes, but they did not express CD19 or CD11b. In human bone marrow, only 1.5±0.19% of lymphocytes expressed EphB6. Compared with the expression in peripheral lymphocytes, prominent expression of EphB6 protein was demonstrated in CD4ィイD1+ィエD1 CD8ィイD1+ィエD1 double-positive mouse thymocytes. The T-cell lineage-specific expression was strictly conserved in human leukemia/lymphoma cells. Among T-cell-derived leukemia cells, the expression level of EphB6 seemed to decrease with maturation of the cells. These results suggest that EphB6 expression is regulated in T-cell development. Less