BACKGROUND: The ternary complex factors (TCFs; Elk1, Net, and Sap-1) are growth factor-responsive transcription cofactors of serum response factor (SRF) and are activated by MAP kinase (MAPK) phosphorylation to regulate immediate early gene transcription. Although cell adhesion also can regulate immediate early genes and proliferation, the mechanism for this effect has remained unexplored. RESULTS: Restricting adhesion and spreading of G(0)-synchronized cells on substrates with decreasing size of micropatterned islands of fibronectin suppressed serum-induced immediate early gene expression and S phase entry. Knockdown of Sap-1 decreased expression of the immediate early genes egr1 and fos and subsequent proliferation normally present with high adhesion, whereas knockdown of Net rescued egr1 and fos expression and proliferation normally suppressed by low adhesion. Chromatin immunoprecipitation studies showed increased occupancy of egr1 and fos promoters by Sap-1 with high adhesion, whereas low adhesion increased Net occupancy. This switch in TCF promoter binding was regulated by an adhesion-mediated switch in MAPK activity. Increasing adhesion enhanced serum-induced JNK activity while suppressing p38 activity, leading to increased Sap-1 phosphorylation and Net dephosphorylation, and switching Net with Sap-1 at egr1 and fos promoters to support proliferation. Microarray studies confirmed this switch in TCF regulation of proliferative genes and uncovered novel gene targets and functions coregulated by Sap-1 and Net. CONCLUSIONS: These data demonstrate a key role for the TCFs in adhesion-induced transcription and proliferation and reveal a novel MAPK/TCF transcriptional switch that controls this process.