MUC13 interaction with receptor tyrosine kinase HER2 drives pancreatic ductal adenocarcinoma progression.
Although MUC13, a transmembrane mucin, is aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC) and generally correlates with increased expression of HER2, the underlying mechanism remains poorly understood. Herein, we found that MUC13 co-localizes and interacts with HER2 in PDAC cells (reciprocal co-immunoprecipitation, immunofluorescence, proximity ligation, co-capping assays) and tissues (immunohistofluorescence). The results from this study demonstrate that MUC13 functionally interacts and activates HER2 at p1248 in PDAC cells, leading to stimulation of HER2 signaling cascade, including ERK1/2, FAK, AKT and PAK1 as well as regulation of the growth, cytoskeleton remodeling and motility, invasion of PDAC cells-all collectively contributing to PDAC progression. Interestingly, all of these phenotypic effects of MUC13-HER2 co-localization could be effectively compromised by depleting MUC13 and mediated by the first and second EGF-like domains of MUC13. Further, MUC13-HER2 co-localization also holds true in PDAC tissues with a strong functional correlation with events contributing to increased degree of disorder and cancer aggressiveness. In brief, findings presented here provide compelling evidence of a functional ramification of MUC13-HER2: this interaction could be potentially exploited for targeted therapeutics in a subset of patients harboring an aggressive form of PDAC.
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
S
S
Khan
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
M
M
Sikander
Cancer Biology Research Center, Sanford Research, Sioux Falls, SD, USA.
M C
MC
Ebeling
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
A
A
Ganju
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
S
S
Kumari
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
M M
MM
Yallapu
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
B B
BB
Hafeez
Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki City, Osaka, Japan.
T
T
Ise
Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki City, Osaka, Japan.
S
S
Nagata
Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA.
N
N
Zafar
Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA.
S W
SW
Behrman
Department of Biostatistics & Epidemiology, University of Tennessee Health Science Center, Memphis, TN, USA.
J Y
JY
Wan
Department of Physics, University of Memphis, Memphis, TN, USA.
H M
HM
Ghimire
Department of Physics, University of Memphis, Memphis, TN, USA.
P
P
Sahay
Department of Physics, University of Memphis, Memphis, TN, USA.
P
P
Pradhan
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
S C
SC
Chauhan
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
M
M
Jaggi
D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D006801:Humans; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D009077:Mucins; D018719:Erb-b2 Receptor Tyrosine Kinases; C429552:MUC13 protein, human; C508053:ERBB2 protein, human