Loss of Keratin 8 Phosphorylation Leads to Increased Tumor Progression and Correlates with Clinico-Pathological Parameters of OSCC Patients

Alam, Hunain; Gangadaran, Prakash; Bhate, Amruta; Chaukar, Devendra; Sawant, Sharada; Tiwari, Richa; Bobade, Jyoti; Kannan, Sadhana; D’Cruz, Anil; Kane, Shubhada; Vaidya, Milind M.

doi:10.1371/journal.pone.0027767

Cited by 36 publications

(41 citation statements)

References 45 publications

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“…Genome-wide association studies have also identified single nucleotide polymorphisms in the human K5 locus that are correlated with an increased lifetime risk of developing basal cell carcinoma (Stacey et al 2009). As already discussed above, keratin phosphorylation, affecting cell motility, is also implicated in cancer cell migration and metastasis (Alam et al 2011;Busch et al 2012).…”

Section: Keratins and Cancermentioning

confidence: 83%

“…K8 phosphorylation is implicated in both inhibition and promotion of cell migration, depending on cell type and stimulus (Chung et al 2013). It is linked to increased migration in pancreatic and gastric cells but decreased migration in oral squamous carcinoma cells (Alam et al 2011;Busch et al 2012), highlighting the stimulus-specific function of phosphorylation. In response to cell stress (such as under UV radiation and in apoptosis) or disease (psoriasis and squamous cell carcinoma), K4, K5 and K6 undergo phosphorylation, causing keratin filaments to be disassembled into granules, allowing for short-term regulation of epithelial cell plasticity (Fois et al 2013).…”

Section: Post-translational Modificationsmentioning

confidence: 99%

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Keratins and skin disease

2015

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Mutations in keratin genes cause a diverse spectrum of skin, hair and mucosal disorders. Cutaneous disorders include epidermolysis bullosa simplex, palmoplantar keratoderma, epidermolytic ichthyosis and pachyonychia congenita. Both clinical and laboratory observations confirm a major role for keratins in maintaining epidermal cell-cell adhesion. When normal tissue homeostasis is disturbed, for example, during wound healing and cancer, keratins play an important non-mechanical role. Post-translational modifications including glycosylation and phosphorylation of keratins play an important role in protection of epithelial cells from injury. Keratins also play a role in modulation of the immune response. A current focus in the area of keratins and disease is the development of new treatments including small inhibitory RNA (siRNA) to mutant keratins and small molecules to modulate keratin expression.

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Section: Keratins and Cancermentioning

confidence: 83%

Section: Post-translational Modificationsmentioning

confidence: 99%

Keratins and skin disease

2015

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“…Numerous vimentin phosphorylation sites have been identified in vivo 8 and they appear to promote its pro-migratory function, in part by enhancing recycling 87 and activation 88 of integrins. K8 phosphorylation at Ser432 has been linked to increased migration of pancreatic and gastric cells 89 but decreased migration of oral squamous carcinoma cells 90 , highlighting a context-specific function of this phospho-residue. Increased cellular elasticity caused by the bioactive lipid sphingosylphosphorylcholine, 91 which was used in the study of pancreatic and gastric cells, likely orchestrates a unique migratory program that is dependent on pSer432-mediated perinuclear K8 and K18 re-reorganization.…”

Section: If Phosphorylation: Multifunctional Ptmmentioning

confidence: 99%

Post-translational modifications of intermediate filament proteins: mechanisms and functions

Snider

Omary

2014

Nat Rev Mol Cell Biol

443

426

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Preface Intermediate filaments (IFs) are cytoskeletal and nucleoskeletal structures that provide mechanical and stress-coping resilience to cells, contribute to subcellular and tissue-specific biological functions, and facilitate intracellular communication. IF proteins, including nuclear lamins and cytoplasmic keratins, vimentin, desmin, neurofilaments, and glial fibrillary acidic protein, undergo various functionally important post-translational modifications (PTMs). Proteomic advances highlight the enormous complexity of IF PTMs, which include phosphorylation, glycosylation, sumoylation, acetylation, and prenylation, as well as their ability to regulate IF proteins, and are likely to reveal novel modifications. We would like to keep the original statement, since the revised version seems to imply that proteomic advances provide insight into the ability of PTMs to regulate IF proteins, which is not the case. Future studies will need to characterize their on–off mechanisms, cross-talk, and utility as biomarkers and targets for diseases involving the IF cytoskeleton.

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“…An inhibitory influence for K8 towards cell migration is suggested by studies in which pancreatic cancer cells [89] and a poorly invasive subclone of MDA-MB-468 breast cancer cells was subjected to K8 knockdown [90], a highly invasive subclone of MDA-MB-435 breast cancer cells was made to overexpress K8 [90], and when KLE endometrial cancer cells and HepG2 hepatocellular cancer cells were subjected to K8/K18 silencing [91]. Other studies related the loss of K8 phosphorylation at either Ser 73 or Ser 431 to increase migration and/or metastatic potential for oral squamous cell carcinoma cells [92] and colorectal cancer cells [93]. The opposite outcome, i.e., K8-dependent stimulation of cell migration, was inferred from the impaired collective migration of hepatoma cells following K8 silencing [35].…”

Section: The Complex Relationship Between Keratins 8/18 and Epitheliamentioning

confidence: 99%

Networking galore: intermediate filaments and cell migration

Chung

Rotty

Coulombe

2013

Current Opinion in Cell Biology

167

149

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Intermediate filaments (IFs) are assembled from a diverse group of evolutionarily conserved proteins and are specified in a tissue-, cell type-, and context-dependent fashion in the body. IFs are involved in multiple cellular processes that are crucial for the maintenance of cell and tissue integrity and the response and adaptation to various stresses, as conveyed by the broad array of crippling clinical disorders caused by inherited mutations in IF coding sequences. Accordingly, the expression, assembly and organization of IFs are tightly regulated. Migration is a fitting example of a cell-based phenomenon in which IFs participate as both effectors and regulators. With a particular focus on vimentin and keratin, we here review how the contributions of IFs to the cell’s mechanical properties, to cytoarchitecture and adhesion, and to regulatory pathways collectively exert a significant impact on cell migration.

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Loss of Keratin 8 Phosphorylation Leads to Increased Tumor Progression and Correlates with Clinico-Pathological Parameters of OSCC Patients

Cited by 36 publications

References 45 publications

Keratins and skin disease

Keratins and skin disease

Post-translational modifications of intermediate filament proteins: mechanisms and functions

Networking galore: intermediate filaments and cell migration

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