title: Dysregulation of splicing proteins in head and neck squamous cell carcinoma.
abstract: Signaling plays an important role in regulating all cellular pathways. Altered signaling is one of the hallmarks of cancers. Phosphoproteomics enables interrogation of kinase mediated signaling pathways in biological systems. In cancers, this approach can be utilized to identify aberrantly activated pathways that potentially drive proliferation and tumorigenesis. To identify signaling alterations in head and neck squamous cell carcinoma (HNSCC), we carried out proteomic and phosphoproteomic analysis of HNSCC cell lines using a combination of tandem mass tag (TMT) labeling approach and titanium dioxide-based enrichment. We identified 4,920 phosphosites corresponding to 2,212 proteins in six HNSCC cell lines compared to a normal oral cell line. Our data indicated significant enrichment of proteins associated with splicing. We observed hyperphosphorylation of SRSF protein kinase 2 (SRPK2) and its downstream substrates in HNSCC cell lines. SRPK2 is a splicing kinase, known to phosphorylate serine/arginine (SR) rich domain proteins and regulate splicing process in eukaryotes. Although genome-wide studies have reported the contribution of alternative splicing events of several genes in the progression of cancer, the involvement of splicing kinases in HNSCC is not known. In this study, we studied the role of SRPK2 in HNSCC. Inhibition of SRPK2 resulted in significant decrease in colony forming and invasive ability in a panel of HNSCC cell lines. Our results indicate that phosphorylation of SRPK2 plays a crucial role in the regulation of splicing process in HNSCC and that splicing kinases can be developed as a new class of therapeutic target in HNSCC.
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|b Department of Biochemistry and Molecular Biology , Pondicherry University , Puducherry , India.
authors: Aneesha
authors: A
authors: Radhakrishnan
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|c Amrita School of Biotechnology, Amrita University , Kollam , India.
authors: Vishalakshi
authors: V
authors: Nanjappa
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.
authors: Remya
authors: R
authors: Raja
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|d Manipal University , Madhav Nagar, Manipal , India.
authors: Gajanan
authors: G
authors: Sathe
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|d Manipal University , Madhav Nagar, Manipal , India.
authors: Sandip
authors: S
authors: Chavan
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|e Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University , Puducherry , India.
authors: Raja Sekhar
authors: RS
authors: Nirujogi
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|f School of Biotechnology, KIIT University , Bhubaneswar , India.
authors: Arun H
authors: AH
authors: Patil
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|f School of Biotechnology, KIIT University , Bhubaneswar , India.
authors: Hitendra
authors: H
authors: Solanki
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|c Amrita School of Biotechnology, Amrita University , Kollam , India.
authors: Santosh
authors: S
authors: Renuse
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.
authors: Nandini A
authors: NA
authors: Sahasrabuddhe
authors: b Department of Biochemistry and Molecular Biology , Pondicherry University , Puducherry , India.|f School of Biotechnology, KIIT University , Bhubaneswar , India.
authors: Premendu P
authors: PP
authors: Mathur
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|c Amrita School of Biotechnology, Amrita University , Kollam , India.|e Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University , Puducherry , India.|g YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University , Mangalore , India.
authors: T S Keshava
authors: TS
authors: Prasad
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.
authors: Prashant
authors: P
authors: Kumar
authors: h Milton J Dance Head and Neck Center, Greater Baltimore Medical Center , Baltimore , MD , USA.|i Department of Otolaryngology-Head and Neck Surgery , Johns Hopkins University School of Medicine , Baltimore , MD , USA.
authors: Joseph A
authors: JA
authors: Califano
authors: i Department of Otolaryngology-Head and Neck Surgery , Johns Hopkins University School of Medicine , Baltimore , MD , USA.
authors: David
authors: D
authors: Sidransky
authors: j McKusick-Nathans Institute of Genetic Medicine , Baltimore , MD , USA.|k Departments of Biological Chemistry , Baltimore , MD , USA.|l Oncology and Pathology, Johns Hopkins University School of Medicine , Baltimore , MD , USA.|m Pathology, Johns Hopkins University School of Medicine , Baltimore , MD , USA.
authors: Akhilesh
authors: A
authors: Pandey
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|g YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University , Mangalore , India.
authors: Harsha
authors: H
authors: Gowda
authors: a Institute of Bioinformatics, International Technology Park , Bangalore , India.|g YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University , Mangalore , India.
authors: Aditi
authors: A
authors: Chatterjee
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D040901:Proteomics; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; C110522:SRPK2 protein, human
keywords: GeneSpring; SR proteins; in vitro labeling; mRNA processing; phosphorylation; spliceosome