GEF-H1/RhoA/MLC2 signaling is reported to play a role in colon cancer invasion and metastasis (Cao et al., 2019), but the mechanisms are imprecisely understood and the upstream regulation of GEF-H1 is uncertain–the same is true regarding a limited understanding of how upstream signaling may modulate the actions in CRC of GEFT, Ephexin4, and GEF5. The gene discussed is ARHGEF16; the disease is colorectal carcinoma.