Human tropomyosin isoforms in the regulation of cytoskeleton functions

Over the past two decades, extensive molecular studies have identified multiple tropomyosin isoforms existing in all mammalian cells and tissues. In humans, tropomyosins are encoded by TPM1 (alpha-Tm, 15q22.1), TPM2 (beta-Tm, 9p13.2-p13.1), TPM3 (gamma-Tm, 1q21.2) and TPM4 (delta-Tm, 19p13.1) genes. Through the use of different promoters, alternatively spliced exons and different sites of poly(A) addition signals, at least 22 different tropomyosin cDNAs with full-length open reading frame have been cloned. Compelling evidence suggests that these isoforms play important determinants for actin cytoskeleton functions, such as intracellular vesicle movement, cell migration, cytokinesis, cell proliferation and apoptosis. In vitro biochemical studies and in vivo localization studies suggest that different tropomyosin isoforms have differences in their actin-binding properties and their effects on other actin-binding protein functions and thus, in their specification ofactin microfilaments. In this chapter, we will review what has been learned from experimental studies on human tropomyosin isoforms about the mechanisms for differential localization and functions of tropomyosin. First, we summarize current information concerning human tropomyosin isoforms and relate this to the functions of structural homologues in rodents. We will discuss general strategies for differential localization oftropomyosin isoforms, particularly focusing on differential protein turnover and differential isoform effects on other actin binding protein functions. We will then review tropomyosin functions in regulating cell motility and in modulating the anti-angiogenic activity of cleaved high molecular weight kininogen (HKa) and discuss future directions in this area.