Nuclear envelope localization of Ran-binding protein 2 and Ran-GTPase-activating protein 1 in psoriatic epidermal keratinocytes.
The nuclear localization signal (NLS)-containing proteins LEDGF and STAT3 localize to the nucleus in both the spinous and basal layers of the epidermis in psoriatic skin, where they function as transcription factors or co-factors to activate epidermal keratinocytes (KCs). However, the mechanism underlying the localization of these proteins remains to be elucidated. We investigated the differential nucleocytoplasmic transport of NLS-containing proteins as a potential pathogenic mechanism for psoriasis vulgaris. Nucleoporins play an important role in the Ran-GTP-dependent nucleocytoplasmic transport of NLS-containing proteins. We showed, using immunohistochemical staining, that the nucleoporins Ran-binding protein 2 (RanBP2) and Ran-GTPase-activating protein 1 (RanGAP1) have greater expression on the nuclear envelope in psoriatic epidermal KCs than in KCs from healthy controls. We then studied the signalling pathways involved in the regulation of these proteins in HaCaT cells. The two major downstream pathways of epidermal growth factor receptor (EGFR) signalling activated in psoriatic KCs are the MAPK/Erk/1/2 and the phosphatidylinositol-3-kinase/Akt pathways. Therefore, we treated HaCaT cells with inhibitors to disrupt the MAP kinase kinase 1 (MEK1), PI3-kinase, or mTOR pathways. RanBP2 and RanGAP1 protein expression levels were significantly greater in the nuclear envelope of HaCaT cells that were not treated with inhibitors than in cells treated with a combination of PI3-kinase and MEK1 inhibitors or mTOR and MEK1 inhibitors. These results suggest that adequate nuclear envelope expression of RanBP2 and RanGAP1 could be a prerequisite for nucleocytoplasmic transport in KCs in psoriatic epidermis.
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kayo
K
Yasuda
Kazumitsu
K
Sugiura
Takuya
T
Takeichi
Yasushi
Y
Ogawa
Yoshinao
Y
Muro
Masashi
M
Akiyama
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004817:Epidermis / Q000473:pathology*; D066246:ErbB Receptors / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000032:analysis*; D006801:Humans; D015603:Keratinocytes / Q000737:chemistry* / Q000648:ultrastructure; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2 / Q000378:metabolism; D018832:Molecular Chaperones / Q000032:analysis*; D009685:Nuclear Envelope / Q000737:chemistry* / Q000648:ultrastructure; D028861:Nuclear Pore Complex Proteins / Q000032:analysis*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011565:Psoriasis / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D020690:GTPase-Activating Proteins; D064111:Minichromosome Maintenance Complex Component 2; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; C504649:PSIP1 protein, human; C092317:RANGAP1 protein, human; C494086:STAT3 protein, human; C094493:ran-binding protein 2; C084859:MCM2 protein, human
MAPK/ERK1/2; PI3K/Akt; Ran-GTPase-activating protein 1; Ran-binding protein 2; keratinocyte; psoriasis vulgaris