Reaching for the STARs

Abstract

The prototype STAR (Signal Transduction and Activation of RNA) protein is Sam68, the Src-associated substrate during mitosis of 68 kDa. Sam68, like all other STAR proteins, belongs to the large class of heteronuclear ribonucleoprotein particle K (hnRNP K) homology (KH) domain family of RNA-binding proteins. The KH domain is an evolutionarily conserved RNA binding domain that consists of 70-100 amino acids. The KH domain is one of the most prevalent RNA binding domains that directly contacts single-stranded RNA with a signature topology. Sam68 contains a single KH domain that harbors additional conserved N- and C-terminal sequences also required for RNA binding specificity and dimerization. Sam68 frequently contains post-translational modifications including serine/threonine, tyrosine phosphorylation, lysine acetylation, arginine methylation and sumoylation. The phosphorylation of Sam68 or its association with SH3 domain containing proteins has been shown to influence its RNA binding activity. Hence Sam68 behaves as a STAR protein, whereby extracellular signals influence its ability to regulate RNA metabolism. Studies in mice have revealed physiological roles linking Sam68 to osteoporosis, cancer, infertility and ataxia. The role of Sam68, a closely related family member quaking (QKI), the KH domain and their links with human disease will be discussed in the present chapter.