MAPK signaling to the early secretory pathway revealed by kinase/phosphatase functional screening.
To what extent the secretory pathway is regulated by cellular signaling is unknown. In this study, we used RNA interference to explore the function of human kinases and phosphatases in controlling the organization of and trafficking within the secretory pathway. We identified 122 kinases/phosphatases that affect endoplasmic reticulum (ER) export, ER exit sites (ERESs), and/or the Golgi apparatus. Numerous kinases/phosphatases regulate the number of ERESs and ER to Golgi protein trafficking. Among the pathways identified, the Raf-MEK (MAPK/ERK [extracellular signal-regulated kinase] kinase)-ERK cascade, including its regulatory proteins CNK1 (connector enhancer of the kinase suppressor of Ras-1) and neurofibromin, controls the number of ERESs via ERK2, which targets Sec16, a key regulator of ERESs and COPII (coat protein II) vesicle biogenesis. Our analysis reveals an unanticipated complexity of kinase/phosphatase-mediated regulation of the secretory pathway, uncovering a link between growth factor signaling and ER export.
Farhan
Hesso
H
Biozentrum, Universität Basel, 4056 Basel, Switzerland.
Wendeler
Markus W
MW
Mitrovic
Sandra
S
Fava
Eugenio
E
Silberberg
Yael
Y
Sharan
Roded
R
Zerial
Marino
M
Hauri
Hans-Peter
HP
D000818:Animals; D022181:COP-Coated Vesicles / Q000378:metabolism; D016208:Databases, Factual; D004721:Endoplasmic Reticulum / Q000378:metabolism; D036681:Fluorescence Recovery After Photobleaching; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D055571:Secretory Pathway / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
C084004:LMAN1 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; D010770:Phosphotransferases; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases