Suppressor of cytokine signaling 1 interacts with the macrophage colony-stimulating factor receptor and negatively regulates its proliferation signal

Macrophage colony-stimulating factor receptor (M-CSF-R) is a tyrosine kinas e that regulates proliferation, differentiation, and cell survival during m onocytic lineage development. Upon activation, M-CSF-R dimerizes and autoph osphorylates on specific tyrosines, creating binding sites for several cyto plasmic SH2-containing signaling molecules that relay and modulate the M-CS F signal. Here we show that M-CSF-R interacts with suppressor of cytokine s ignaling 1 (Socs1), a negative regulator of various cytokine and growth fac tor signaling pathways. Using the yeast two-hybrid system, in vitro glutath ione S-transferase-M-CSF-R pull-down, and in vivo coimmunoprecipitation exp eriments, we demonstrated a direct interaction between the SH2 domain of So cs1 and phosphorylated tyrosines 697 or 721 of the M CSF-R kinase insert re gion. Moreover, Socs1 is tyrosine-phosphorylated in response to M-CSF. Ecto pic expression of Socs1 in FDC-P1/MAC and EML hematopoietic cell lines decr eased their growth rates in the presence of limiting concentrations of M-CS F. However, Socs1 expression did not totally suppress long term cell growth in the presence of saturating M-CSF concentrations, in contrast to other c ytokines such as stem cell factor and interleukin 3. Taken together, these results suggest that Socs1 is an M-CSF-R-binding partner involved in negati ve regulation of proliferation signaling and that it differentially affects cytokine receptor signals.