Page 27 - Annual Report 2020
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                     molecular and cellular level, active FAK (phosphor- ylated FAK at tyrosine 397) bound to TGFβR2 and kept TGFβR2 at the peripheral plasma membrane of HSCs, and it induced TGFβR2 phosphoryla- tion at tyrosine 336. In contrast, targeting FAK or mutating Y336 to F on TGFβR2 led to lysosomal sorting and degradation of TGFβR2. Using RNA sequencing, we identified that the transcripts of 764 TGFβ target genes were influenced by FAK in- hibition, and that through FAK, TGFβ1 stimulated HSCs to produce a panel of tumor-promoting factors, including extracellular matrix remodel-
ing proteins, growth factors and cytokines, and immune checkpoint molecule PD-L1. Functionally, targeting FAK inhibited tumor promoting effects of HSCs in vitro and in a tumor implantation
in vivo model. These data have been published in Hepatology Communications.
In addition, we investigated the role of protein di- aphanous homolog 1 (known as Diaph1 or mDia1) for the myofibroblastic activation of HSCs in the last year. We found that the inactivation of Diaph1 blocked internalization and intracellular trafficking of TGFβRII and reduced SMAD3 phosphorylation induced by TGFβ1. Mechanistic studies revealed that the N-terminal portion of Diaph1 interacted with both TGFβRII and Rab5a directly and that Rab5a activity of HSCs was increased by Diaph1 overexpression and decreased by Diaph1 knock- down. Additionally, expression of Rab5aQ79L (active Rab5a mutant) increased whereas the expression of Rab5aS34N (inactive mutant) reduced the endosomal localization of TGFβRII
in HSCs compared to the expression of wild-type Rab5a. Functionally, TGFβ stimulation promoted HSCs to express tumor-promoting factors, and α-smooth muscle actin, fibronection, and CTGF,
markers of myofibroblastic activation of HSCs. Targeting Diaph1 or Rab5a suppressed HSC activation and limited tumor growth in a tumor implantation in vivo model. Thus, Dipah1 and Rab5a represent targets for inhibiting HSC acti- vation and the hepatic tumor microenvironment. These data have been published in FASEB J.
 Other professional activities:
NIH Grant Review:
2020 NIH the Innovative Research in Cancer Nanotechnology (IRCN) Study Section, ad hoc reviewer
 Publications:
1. ChenY,LiQ,TuK,WangY,WangX,LiuD,ChenC,LiuD, Yang R, Qiu W, Kang N. Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2. Hepatol Commun. 2019 Dec 20;4(2):268-283. doi: 10.1002/ hep4.1452. eCollection 2020 Feb. PMID: 32025610.
2. LiuD,FuX,WangY,WangX,WangH,WenJ,KangN. Protein Diaphanous Homolog 1 (Diaph1) Promotes Myofibroblastic Activation of Hepatic Stellate Cells by Regulating Rab5a Activity and TGFβ Receptor Endocytosis. FASEB J. 2020 Jun;34(6):7345-7359. doi: 10.1096/ fj.201903033R. Epub 2020 Apr 18. PMID: 32304339
3. Kang N. Mechanotransduction in Liver diseases.
Semin Liver Dis. 2020 Feb; 40(1): 84–90. PMID: 31683318
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