Differential transmission of MEKK1 morphogenetic signals by JNK1 and JNK2.
JNK1 and JNK2 are two ubiquitously expressed isoforms that exert redundant roles in many physiological processes, but the extent of their relative contributions to these processes has not been well characterized. We show that both JNK isoforms transmit MEK kinase 1 (MEKK1)-mediated morphogenetic signals during mouse embryonic eyelid closure. However, JNK1 and JNK2 are not synonymous, because MEKK1 is haploinsufficient for normal eyelid closure in Jnk1-null mice, but is haplosufficient in Jnk2-null mice. In the Mekk1 heterozygous background, a more efficient phosphorylation of JNK1 than JNK2 leads to differential downstream reactions, such as c-Jun phosphorylation and PAI1 expression in the developing eyelid epithelium. Differences in efficiency of phosphorylation are attributed to JNK1 Gly177 and Ser179 -- residues that are absent in JNK2 -- which promote a less ordered structural conformation. This leads to more favorable JNK phosphorylation by activin B morphogenetic signals mediated by the MEKK1-MKK4 pathway. Interestingly, Mekk1-Jnk1-Jnk2 triple hemizygotes display a partial eye-open phenotype at birth, suggesting that all three genes dose-dependently contribute to morphogenetic eyelid closure. We propose that a MEKK1-JNK1/2 axis governs the JNK activation levels to control downstream transcriptional events and eyelid morphogenesis and that reduction of upstream MEKK1 signals uncovers analogous but differential roles of JNK1 and JNK2 in a biological process.
Takatori
Atsushi
A
Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Geh
Esmond
E
Chen
Liang
L
Zhang
Lin
L
Meller
Jarek
J
Xia
Ying
Y
D000818:Animals; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D005143:Eyelids / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation
D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D048728:MAP Kinase Kinase Kinase 1