UC San Diego

Chronic lymphocytic leukemia (CLL) is one of the most common leukemia that derives from the mutations of B lymphocyte. Previous research has shown that the receptor tyrosine kinase-like orphan receptor 1(ROR1), the receptor expressed specifically by the CLL, is induced to recruit guanine nucleotide exchange factors 2 (ARHGEF2) once activated by Wnt5a, the ligand that bind and activates ROR1 to promote the proliferation and migration of CLL. However, the mechanism for recruiting ARHGEF2 remain unclear. In this study, we found that 14-3-3ζ, one isomer of the 14-3-3 scaffold protein family, helps to recruit guanine nucleotide exchange factor 2 (ARHGEF2), on to the ROR1 receptor in CLL. Here, we reveal that 14-3-3ζ interacts with both ROR1 and ARHGEF2 separately in CLL. Upon Wnt5a stimulation, 14-3-3ζ is anchored onto ROR1 via its S857 motif. Also, 14-3-3ζ is required for the Wnt5a-induced recruitment of ARHGEF2 onto ROR1. Lastly, 14-3-3ζ is necessary for the RhoA/Rac1 activation by ARHGEF2 and proliferation/migration induced by RhoA/Rac1 activation. Collectively, 14-3-3ζ mediates the recruitment of ARHGEF2 onto ROR1, which facilitates the Wnt5a-induced CLL proliferation/migration.