Recent progress has been made on the role of oncoproteins c-Ski and related SnoN 
in the control of cellular transformation. c-Ski/SnoN potently repress 
transforming growth factor-beta (TGF-beta) antiproliferative signaling through 
physical interaction with signal transducers called Smads. Overexpression of 
c-Ski/SnoN also induces skeletal muscle differentiation, but how c-Ski/SnoN 
function in myogenesis is largely unknown. During our investigation on the role 
of sumoylation in TGF-beta signaling, we inadvertently found that SnoN is 
modified by small ubiquitin-like modifier-1 (SUMO-1). Here, we biochemically 
characterize SnoN sumoylation in detail and report the physiological function of 
the modification. Sumoylation occurs primarily at lysine 50 (Lys-50). PIAS1 and 
PIASx proteins physically interact with SnoN to stimulate its sumoylation, thus 
serving as SUMO-protein isopeptide ligases (E3) for SnoN sumoylation. SnoN 
sumoylation does not alter its metabolic stability or its ability to repress 
TGF-beta signaling. Notably, loss of sumoylation in the Lys-50 site (via a 
Lys-to-Arg point mutation) potently activates muscle-specific gene expression 
and enhances myotube formation. Our study suggests a novel role for SUMO 
modification in the regulation of myogenic differentiation.