TY - JOUR
T1 - The STAT3 beacon
T2 - IL-6 recurrently activates STAT 3 from endosomal structures
AU - German, Christopher L.
AU - Sauer, Brian M.
AU - Howe, Charles L.
N1 - Funding Information:
We thank Dr. Bruce Horazdovsky, Dr. Zhiguo Zhang, Dr. Keith Bible, and Dr. Dan Billadeau for providing materials, Dr. Larry Pease and Dr. Jennifer Westendorf for the use of equipment, and Mike Bell for his assistance with electroporation. Mary Pendergast, Reghann Corey, Kim Cook, Rachel Bergstrom and Dr. William Schmalstieg have been invaluable in their critical reading of this manuscript. This work was supported by Donald and Frances Herdrich (CLH) and an early career development award from Mayo Clinic (CLH) . CLG was supported by the Mayo Graduate School and the Kern Predoctoral Neuroscience Fellowship .
PY - 2011/8/15
Y1 - 2011/8/15
N2 - Endocytic trafficking plays an important role in signal transduction. Signal transducer and activator of transcription 3 (STAT3) and mitogen-activate protein kinase (MAPK) have both been localized to endosomal structures and are dependent upon endocytosis for downstream function. While the dependence of MAPK signaling upon endosomes has been well characterized, the involvement of endosomes in regulating STAT3 signaling has not been defined. Consequently, this study evaluated the role of endosomes in the initiation, modulation, amplification and persistence of interleukin-6(IL-6)-induced STAT3 signal transduction and transcription, and utilized IL-6-induced MAPK signaling as a comparator. Using pharmacologic treatment and temperature control of endocytic trafficking, pulse-chase treatments and in vitro kinase assays, STAT3 was found to interact with endosomes in a markedly different fashion than MAPK. STAT3 was activated by direct interaction with internal structures upstream of the late endosome following IL-6 exposure and persistent STAT3 signaling depended upon recurrent activation from endocytic structures. Further, STAT3 subcellular localization was not dependent upon endocytic trafficking. Instead, STAT3 transiently interacted with endosomes and relocated to the nucleus by an endosome-independent mechanism. Finally, endocytic trafficking played a central role in regulating STAT3 serine 727 phosphorylation through crosstalk with the MAPK signaling system. Together, these data reveal endosomes as central to the genesis, course and outcome of STAT3 signal transduction and transcription.
AB - Endocytic trafficking plays an important role in signal transduction. Signal transducer and activator of transcription 3 (STAT3) and mitogen-activate protein kinase (MAPK) have both been localized to endosomal structures and are dependent upon endocytosis for downstream function. While the dependence of MAPK signaling upon endosomes has been well characterized, the involvement of endosomes in regulating STAT3 signaling has not been defined. Consequently, this study evaluated the role of endosomes in the initiation, modulation, amplification and persistence of interleukin-6(IL-6)-induced STAT3 signal transduction and transcription, and utilized IL-6-induced MAPK signaling as a comparator. Using pharmacologic treatment and temperature control of endocytic trafficking, pulse-chase treatments and in vitro kinase assays, STAT3 was found to interact with endosomes in a markedly different fashion than MAPK. STAT3 was activated by direct interaction with internal structures upstream of the late endosome following IL-6 exposure and persistent STAT3 signaling depended upon recurrent activation from endocytic structures. Further, STAT3 subcellular localization was not dependent upon endocytic trafficking. Instead, STAT3 transiently interacted with endosomes and relocated to the nucleus by an endosome-independent mechanism. Finally, endocytic trafficking played a central role in regulating STAT3 serine 727 phosphorylation through crosstalk with the MAPK signaling system. Together, these data reveal endosomes as central to the genesis, course and outcome of STAT3 signal transduction and transcription.
KW - Erk1/2
KW - IL-6
KW - MAPK
KW - STAT3
KW - Signaling endosome
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U2 - 10.1016/j.yexcr.2011.05.009
DO - 10.1016/j.yexcr.2011.05.009
M3 - Article
C2 - 21619877
AN - SCOPUS:79960081111
SN - 0014-4827
VL - 317
SP - 1955
EP - 1969
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 14
ER -