Model for induction of specific signals by G-CSF versus M-CSF that contribute to myeloid lineage specification. GCSFR signals specifically activate STAT3 and SHP2. The latter has been shown to dephosphorylate and so inhibit ICSBP cooperation with PU.1, favoring granulopoiesis. MCSFR signals specifically activate PLCγ2 and thereby PKC, leading to more potent ERK activation than occurs via GCSFR-mediated SHP2 activation. As a result, M-CSF signaling more readily stabilizes c-Fos, phosphorylates C/EBPα(S21), and stimulates terniary complex factor (TCF)–mediated Egr-1/2 transcription, each favoring monopoiesis. Reduced phosphorylation of C/EBPα(S21) via G-CSF signaling strengthens its ability to direct granulopoiesis as a homodimer, whereas P-C/EBPα(S21) retains the capacity to induce monopoiesis as a heterodimer with c-Jun or c-Fos.