Dk. Wooten et al., Cytokine signaling through Stat3 activates integrins, promotes adhesion, and induces growth arrest in the myeloid cell line 32D, J BIOL CHEM, 275(34), 2000, pp. 26566-26575
Hematopoietic cell development and function is dependent on cytokines and o
n intercellular interactions with the microenvironment. Although the intrac
ellular signaling pathways stimulated by cytokine receptors are well descri
bed, little is known about the mechanisms through which these pathways modu
late hematopoietic cell adhesion events in the microenvironment. Here we sh
ow that cytokine-activated Stats stimulates the expression and function of
cell surface adhesion molecules in the myeloid progenitor cell line 32D. We
generated an erythropoietin receptor (EpoR) isoform (ER343/401-S3) that ac
tivates Stats rather than Stat5 by substituting the Stats binding/activatio
n sequence motif from gp130 for the sequences surrounding tyrosines 343 and
401 in the receptor cytoplasmic region, Activation of Stats leads to homot
ypic cell aggregation, increased expression of intercellular adhesion molec
ule 1 (ICAM-1), CD18, and CD11b, and activation of signaling through CD18-c
ontaining integrins. Unlike the wild type EpoR, ER343/401-S3 is unable to s
upport long term Epo-dependent proliferation in 32D cells. Instead, Epo-tre
ated ER343/401-S3 cells undergo G(1) arrest and express elevated levels of
the cyclin-dependent kinase inhibitor p27(Kip1). Sustained activation of St
ats in these cells is required for their altered morphology and growth prop
erties since constitutive SOCS3 expression abrogates homotypic cell aggrega
tion, signaling through CD18-containing integrins, G(1) arrest, and accumul
ation of p27(Kip1). Collectively, our results demonstrate that cytokine-act
ivated Stats stimulates the expression and function of cell surface adhesio
n molecules, indicating that a role for Stats is to regulate intercellular
contacts in myeloid cells.