AKRL1 and AKRL2 activate the JNK pathway

Background: c‐Jun N‐terminal kinase (JNK), a member of the mitogen‐activated protein kinase (MAPK) family, is activated by specific cytokines and various environmental stresses. MKK4 and MKK7 are shown to be direct activators of JNK. Although several upstream components of the JNK pathway, including members of the MAPKKK family have been described, the components lying between the receptors or sensors and JNK have not been fully characterized. Results: We have identified AKRL1 and AKRL2 (Akr1p‐like 1 and 2) as novel activators of the JNK pathway. AKRL1 and AKRL2 proteins have a considerable sequence similarity to Akr1p, a protein essential for endocytosis in Saccharomyces cerevisiae. Expression of AKRL1 or AKRL2 activates JNK and its activators MKK4 and MKK7. This AKRL1/2‐induced JNK activation is significantly suppressed by the expression of a kinase‐negative mutant of TAK1, a member of the MAPKKK family. AKRL1 and AKRL2 localize to the Golgi. Both the N‐terminal half and the C‐terminal transmembrane domain of AKRL1/2 are required for the JNK activation. The C‐terminal transmembrane domain of AKRL1/2 is required for localization to the Golgi. Conclusion: AKRL1 and AKRL2 are localized to Golgi and the novel activators of the JNK pathway.