Membrane receptor signaling by various ligands induces activation of Jak kinases which then leads to tyrosine phosphorylation of the various Stat transcription factors. Stat1 and Stat2 are induced by IFN-a and form a heterodimer which is part of the ISGF3 transcription factor complex. Although early reports indicate Stat3 activation by EGF and IL-6, it has been shown that Stat3b appears to be activated by both while Stat3a is activated by EGF, but not by IL-6. Highest expression of Stat4 is seen in testis and myeloid cells. IL-12 has been identified as an activator of Stat4. Stat5 is activated by prolactin and by IL-3. Stat6 is involved in IL-4 activated signaling pathways.