Functionally Distinct Isoforms of STAT5 Are Generated by Protein Processing

Abstract

The interleukin-3 family of cytokines, which play an important role in the development of myeloid lineages, transduce signals through the JAK-STAT pathway. Previous studies demonstrate that this process entails the activation of four distinct isoforms of STAT5, where two shorter isoforms are activated in a distinct population of cells. We now demonstrate that the shorter isoforms represent carboxy-terminal truncations. Moreover, these truncations are not generated by RNA processing, but by a specific proteolytic activity. Consistent with the notion that truncated STAT5 isoforms transduce distinct signals, they fail to promote the activation of several known interleukin-3 target genes. These studies suggest that the activity of a specific protease may play a critical role in defining the biological responses transduced by STAT5.

The role of STATs in myeloid differentiation and leukemia

“…Similarly, overexpression of synthetic p77 or p80 in 32D or BaF3 cells blocks the IL-3 induced expression of STAT5 dependent genes, such as CIS and OSM Mui et al, 1996). The same phenomenon is observed when IL-3 induced gene expression is compared between immature and mature murine hematopoietic cells (Azam et al, 1997). In murine cells, p77 and p80 do not result from alternative splicing, but are generated by protein processing.…”

IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line

“…In addition, isoforms of STAT1, STAT3, STAT5A, STAT5B that lack the COOH terminus, a region highly variable among STAT members containing the transactivation domain, have been described. These isoforms arise through an alternative splicing mechanism or a speci®c protein processing and are thought to be natural dominant negative forms of STAT proteins (Schindler et al, 1992;Azam et al, 1995Azam et al, , 1997Caldenhoven et al, 1996;Kazansky et al, 1995;Meyer et al, 1998;Schaefer et al, 1997;Wang et al, 1996).…”

Molecular characterization and IFN signal pathway analysis of Carassius auratus CaSTAT1 identified from the cultured cells in response to virus infection

“…The mechanism for generation of the STAT variants is mostly due to an RNA processing event [7,8], while the two shorter isoforms among four STAT5 variants are generated by a unique and developmentally proteolytic activity [4]. Comparison of the C terminal regions between CaSTAT1 and human STAT1a or STAT1b show that CaSTAT1 is most analogous to human STAT1b because they all lack the C-terminal region characteristic of the site of serine phosphorylation (Fig.…”

“…In mammals, naturally occurring STAT variants have been detected for several STATs, including STAT1 [7,8], STAT3 [5,6], and STAT5 [3,4]. These variants all exhibit truncations in their C-terminal domains, in which the conserved PMSP sequence is missing [12].…”