Shinichi Takayama, M.D., Ph.D.

Principal Scientist

Cancer, Degenerative Muscle Disease
takayama@bbri.org

Research Summary

We are investigating the biological function of molecular chaperone regulators, BAG family proteins.  BAG family proteins interact to 70Kd family of molecular chaperones (Hsp70) and regulate their protein folding activity.  Molecular chaperones and their regulators (co-chaperones) maintain cellular homeostasis against environmental stress, and have critical roles in protein folding, inhibition of protein aggregation and degradation of misfolded proteins.  Findings from these studies will identify roles for BAG family proteins in human diseases, especially degenerative diseases and cancer (Hishiya and Takayama, 2008).

Degenerative Muscle Disease

We generated bag3 gene deletion mice, which showed early lethality with massive muscle degeneration.  Pathological features of muscle degeneration seen in bag3 knockout mice are similar to human disease, called myofibrillar myopathy (Homma et al., 2006).  Recently, identical mutations in bag3 gene were identified in human myofibrillar myopathy patients.  Myofibrillar myopathy is a genetically heterogeneous group of diseases characterized by progressive muscle weakness, and, at a cellular level, disrupted Z-disc structure and myofibrillar degeneration. Using bag3 gene knockdown, rapid myofibrillar degeneration and Z-disc disruption was observed in cardiomyocytes exposed to mechanical stretch.  We found that BAG3 interacts with Hsc70 and increases localization and stabilization of the actin capping protein CapZ at Z-disc F-actin (Hishiya et al., 2010).  Myofibrillar myopathy is sometimes accompanied by cytosolic aggregated protein and believed as aggregation or misfolding disease.  Interestingly, desminopathy, subcategory of myofibrillar myopathy, is caused by mutations of molecular chaperone protein, alpha B crystallin (also called HspB5).  One of our major research interests is to investigate the pathogenesis of myofibrillar myopathy found in bag3 mutations. 

Cancer Biology

Overexpression of BAG1 proteins has been documented in some types of human cancers (Takayama et al., 1998). Pathological elevations in either cytosolic or nuclear BAG1 proteins have been reported, correlating with differences in patient survival. BAG1 or its longer isoform BAG1L have been reported to interact with and regulate the activity of intracellular steroid hormone receptors. Interestingly, the BAG1L protein collaborates with androgen receptor, enhancing its transcriptional activity and rendering this nuclear hormone receptor resistant to anti-androgen drugs.  BAG3 has important function in cancer cell metastasis, through regulating actin cytoskeleton and cell adhesion (Iwasaki et al., 2007).  BAG3 protein is highly expressed in many human epithelial cancer cell lines, especially prostate and breast cancer cells.  Recently, we found BAG3 directly interacts with Rap1 guanine nucleotide exchange factor (PDZGEF2) to regulate integrin-mediated cell adhesion (Iwasaki et al., 2010).  The higher levels of BAG3 protein may be relevant to mechanisms of tumor invasion and metastasis.  We believe the molecular mechanisms of cell motility regulated by BAG3 will give us clues for better understanding of cancer metastasis and effective therapy.

Selected Publications

• Hishiya A, Kitazawa T, Takayama S (2010). BAG3 and Hsc70 interact with actin capping protein CapZ to maintain myofibrillar integrity under mechanical stress. Circulation Research in press.

• Hishiya A, Takayama S (2008). Molecular chaperones as regulators of cell death. Oncogene 27: 6489-506.

• Homma S, Iwasaki M, Shelton GD, Engvall E, Reed JC, Takayama S (2006). BAG3 deficiency results in fulminant myopathy and early lethality. Am J Pathol 169: 761-73.

• Iwasaki M, Homma S, Hishiya A, Dolezal SJ, Reed JC, Takayama S (2007). BAG3 regulates motility and adhesion of epithelial cancer cells. Cancer Res 67: 10252-10259.

• Iwasaki M, Tanaka R, Hishiya A, Homma S, Reed JC, Takayama S (2010). BAG3 directly associates with guanine nucleotide exchange factor of Rap1, PDZGEF2, and regulates cell adhesion. Biochem Biophys Res Commun 400: 413-418.

• Takayama S, Krajewski S, Krajewska M, Kitada S, Zapata JM, Kochel K et al (1998). Expression and location of Hsp70/Hsc-binding anti-apoptotic protein BAG-1 and its variants in normal tissues and tumor cell lines. Cancer Res 58: 3116-3131.

PubMed:
Click here for a list of publications (searches the National Library of Medicine's PubMed database.)