Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes.
Epithelial-to-mesenchymal transition (EMT) underlies cell plasticity and embryonic development and is frequently observed in advanced tumorigenesis. We demonstrated that midkine (MK), a retinoic acid-inducible heparin-binding mitogen, promotes EMT in immortalized HaCaT keratinocytes. We showed that MK binds to the Notch2 receptor in HaCaT keratinocytes. We further found that MK activates Notch2 signaling leading to protein/protein interactions between Hes1 and Jak2/Stat3 intermediates. We thus suggest that MK-induced cross talk of Notch2/Jak2/Stat3 signaling pathways can regulate cell plasticity and motility contributing to the EMT and later stages of tumorigenesis.
Huang
Yiping
Y
Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Hoque
Mohammad Obaidul
MO
Wu
Feng
F
Trink
Barry
B
Sidransky
David
D
Ratovitski
Edward A
EA
D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D053614:Janus Kinase 2 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology*; D008856:Microscopy, Fluorescence; D000078792:Midkine; D009369:Neoplasms / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020798:Two-Hybrid System Techniques
D016207:Cytokines; D017931:DNA Primers; C497764:NOTCH2 protein, human; D051883:Receptor, Notch2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000078792:Midkine; C507924:JAK2 protein, human; D053614:Janus Kinase 2