SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. CIS is involved in the negative regulation of cytokines that signal through the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin 3 (IL3) receptor. Inhibits STAT5 trans-activation by suppressing its tyrosine phosphorylation. May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity). Protein modification; protein ubiquitination. Stably associated with the tyrosine-phosphorylated IL3 receptor beta chain and tyrosine-phosphorylated EPO receptor (EPOR). Expressed in various epithelial tissues. Abundantly expressed in liver and kidney, and to a lesser extent in lung. The tissue distribution of isoforms 1 and 1B is distinct. By a subset of cytokines including EPO/erythropoietin. Association with EPOR may target the protein for proteolysis by the ubiquitin-dependent proteasome pathway. CIS is mainly monubiquitinated (37 kDa form) but may also exist in a polyubiquitinated form (45 kDa). CISH polymorphisms are involved in susceptibility to malaria [MIM:611162]. Genetic variations in CISH are involved in susceptibility to tuberculosis [MIM:607948]. Genetic variations in CISH are associated with susceptibility to bacterial invasion of the blood and define the bacteremia susceptibility locus 2 (BACTS2) [MIM:614383]. Truncated N-terminus.