P311 binds to the latency associated protein and downregulates the expression of TGF-β1 and TGF-β2

S Paliwal, J Shi, U Dhru, Y Zhou, L Schuger - Biochemical and biophysical …, 2004 - Elsevier
S Paliwal, J Shi, U Dhru, Y Zhou, L Schuger
Biochemical and biophysical research communications, 2004Elsevier
P311 is an 8-kDa protein originally found in neurons and muscle. We recently showed that
expression of P311 in NIH 3T3 cells induced a myofibroblast phenotype with low TGF-β1
expression. Here we demonstrate that P311 downregulates not only TGF-β1, but also TGF-
β2, expression, with no effect on TGF-β3. In addition, P311 interacts with TGF-β2 in a yeast
two-hybrid system through a sequence encompassing part of the TGF-β latent associated
protein (LAP) and part of mature TGF-β2. Coimmunoprecipitations demonstrated interaction …
P311 is an 8-kDa protein originally found in neurons and muscle. We recently showed that expression of P311 in NIH 3T3 cells induced a myofibroblast phenotype with low TGF-β1 expression. Here we demonstrate that P311 downregulates not only TGF-β1, but also TGF-β2, expression, with no effect on TGF-β3. In addition, P311 interacts with TGF-β2 in a yeast two-hybrid system through a sequence encompassing part of the TGF-β latent associated protein (LAP) and part of mature TGF-β2. Coimmunoprecipitations demonstrated interaction between P311 and TGF-β1 and 2, but not TGF-β3. Additional coimmunoprecipitations after introducing LAP or mature TGF-β1 into cells demonstrated P311 binding to LAP, but not to mature TGF-β. P311 has a conserved PEST domain, which generally serves as a rapid degradation signal. Deletion of the PEST domain reversed the effect of P311 on TGF-β isoforms. Finally, Smad3 activity was decreased in P311-expressing cells, but was corrected by exogenous TGF-β1 treatment, which also elevated TGF-β1 mRNA level. This suggested that P311 downregulates TGF-β1 and 2 in part by blocking TGF-β autoinduction.
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