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Topical treatment of normal skin with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or its synthetic analogs results in enhanced keratinocyte proliferation. Autocrine growth factors belonging to the epidermal growth factor (EGF) family play a major role in controlling keratinocyte proliferation. 1,25-(OH)2D3 enhanced the autonomous proliferation of HaCaT human keratinocytes in the absence of exogenous growth factors. Autonomous and 1,25-(OH)2D3-stimulated proliferations were inhibited by a specific inhibitor of EGF receptor (EGFR) tyrosine kinase, an EGFR-neutralizing antibody, heparin, the heparin antagonist hexadimethrine, and the proteoglycan sulfation inhibitor chlorate. These results indicate the involvement of proteoglycan-dependent EGFR ligands. The initial events in EGFR (i.e. ErbB1) mitogenic signal transduction are dimer formation with another ErbB protein and tyrosine cross-phosphorylation. By immunoprecipitation followed by Western blotting we showed that ErbB1/ErbB3 heterodimers are the major mitogenic signaling entity in 1,25-(OH)2D3-stimulated cells. 1,25-(OH)2D3 did not affect the levels of the proteoglycan-dependent EGFR ligands amphiregulin and heparin-binding EGF nor the synthesis of proteoglycans, as assessed by 35S labeling and ion exchange chromatography. 1,25-(OH)2D3 caused a marked increase in the cellular contents of ErbB1, ErbB2, and ErbB3 proteins. The increase in ErbB proteins that mediates signal transduction by EGFR ligands can account for the stimulatory effect of 1,25-(OH)2D3 on autonomous keratinocyte proliferation.