Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B0FTZ7 (catenin)
 18,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P120 catenin (p120ctn) belongs to the Armadillo family of proteins, which is implicated in cell-cell adhesion and signal transduction. Owing to alternative splicing and multiple translation initiation codons, several p120ctn isoforms can be expressed from a single gene. All p120ctn isoforms share the central Armadillo repeat domain but have divergent N- and C-termini. Little is known about the biological functions of the different isoforms. In this study, we examined the distribution of various p120ctn isoforms and the consequences of their expression in cultured cells of epidermal origin. Immunohistochemical analysis and western blotting revealed that melanocytes and melanoma cells primarily express the long isoform 1A, whereas keratinocytes express shorter isoforms, especially 3A, which localize to cell-cell adhesion junctions in a calcium-dependent manner. The shortest isoform 4A, which was detected in normal keratinocytes and melanocytes, was generally lost from cells derived from squamous cell carcinomas or melanomas. The C-terminal alternatively spliced exon B was present in the p120ctn transcripts in the colon, intestine and prostate, but was lost in several tumor tissues derived from these organs. To test whether p120ctn isoforms serve in distinct biological functions, we transiently transfected the expression constructs into melanoma cells (1205-Lu) and immortalized keratinocytes (HaCaT). Indeed, distinct domains of p120ctn are responsible for its different biological functions. The prominent branching phenotype was induced equally by isoforms 1A, 2A and 3A, whereas the shortest isoform 4A, which was devoid of the N-terminal domain, completely lacked this ability. Also, the exon-B-encoded sequences, as in the isoform 1AB, were sufficient to abolish the branching phenotype as induced by the isoform 1A. The induction of the branching phenotype cosegregated with the nuclear localization of the p120ctn isoforms 1A, 2A and 3A, whereas the isoforms 4A and 1AB, which were excluded from the nucleus, did not induce the branching phenotype. The N-terminal sequences that contain seven out of eight tyrosine residues, recently characterized as potential candidates for phosphorylation by Src kinase, are required for the nuclear localization and for the formation of the branching phenotype. Finally, expression of the p120ctn isoforms, which caused the branching phenotype, was associated with cellular relocalization of E-cadherin in HaCaT cells. Collectively, we have identified sequences within the p120ctn N-terminus that are prerequisites for both nuclear localization and the p120ctn-induced branching phenotype. Loss of the cytoplasmic pool of p120ctn from tumor cells suggests an important function for such isoforms in normal cells and tissues.
 ...
PMID:Specific sequences in p120ctn determine subcellular distribution of its multiple isoforms involved in cellular adhesion of normal and malignant epithelial cells. 1189 87

P120-catenin is the prototypic member of a subfamily of Armadillo repeat domain (Arm domain) proteins involved in cell-cell adhesion. Interestingly, all members of the p120 subfamily have also been observed in the nucleus, suggesting that they have additional roles that have yet to be determined. Here, we have developed a novel model system for studying the nucleocytoplasmic shuttling capabilities of p120. We show that simultaneous deletion of both of the conventional nuclear localization sequences (NLSs) in p120 had little effect on its nuclear localization. Instead, the Armadillo repeat domain was essential, and deletion of Arm repeat 3 or Arm repeat 5 eliminated nuclear entry despite the presence of both NLSs. In addition, deletion of Arm repeat 8 resulted in constitutive nuclear localization of p120-3A in both E-cadherin-positive and -negative cell lines. Thus, the core shuttling functions are dependent on the Arm domain. We have also identified two regions within the N-terminus of p120 that modulate nuclear shuttling dynamics of p120. In cadherin-deficient cells, normal epithelial morphology could be restored by both WT-E-cadherin and p120 uncoupled E-cadherin mutants, but only WT-E-cadherin strongly reduced nuclear localization of p120. Moreover, structural changes in p120 that reduced its affinity for E-cadherin increased p120 nuclear localization. Thus, reduced shuttling in the presence of E-cadherin is principally due to sequestration, a condition that is probably dynamic under normal circumstances but completely lost in metastatic cells that have downregulated E-cadherin. Notably, Arm repeats 3 and 5 are necessary for both E-cadherin binding and nuclear translocation, indicating that these repeats have dual roles. Surprisingly, in the absence of E-cadherin there was significant colocalization of cytoplasmic p120 with elements of the tubulin cytoskeleton, particularly in perinuclear locations. Depolymerizing microtubules with nocodazole increased nuclear p120, whereas stabilizing tubulin with taxol reduced nuclear p120 and strongly increased p120 association with microtubules. Thus, p120 has intrinsic nucleocytoplasmic shuttling activity that is modulated, in part, by extrinsic factors such as cadherin binding and interactions with the microtubule network.
 ...
PMID:Regulation of p120-catenin nucleocytoplasmic shuttling activity. 1295 69

The construction and maintenance of normal epithelia relies on local signals that guide cells into their proper niches and remove unwanted cells. Failure to execute this process properly may result in aberrant development or diseases, including cancer and associated metastasis. Here, we show that local environment influences the behavior of dCsk-deficient cells. Broad loss of dCsk led to enlarged and mispatterned tissues due to overproliferation, a block in apoptosis, and decreased cadherin-mediated adhesion. Loss of dCsk in discrete patches led to a different outcome: epithelial exclusion, invasive migration, and apoptotic death. These latter phenotypes required sharp differences in dCsk activity between neighbors; dE-cadherin, P120-catenin, Rho1, JNK, and MMP2 mediated this signal. Together, our data demonstrate how the cellular microenvironment plays a central role in determining the outcome of altered dCsk activity, and reveal a role for P120-catenin in a mechanism that protects epithelial integrity by removing abnormal cells.
 ...
PMID:Csk-deficient boundary cells are eliminated from normal Drosophila epithelia by exclusion, migration, and apoptosis. 1639 76

The distinction between lobular and ductal lesions of the breast is important in several circumstances. Diagnostic reproducibility of lobular versus ductal lesions, based on histology alone, is less than optimal. The proper distinction between atypical lobular hyperplasia, lobular carcinoma in situ and low-grade ductal carcinoma in situ is critical for patient management. Patients who have a core biopsy of invasive lobular carcinoma often have preoperative magnetic resonance imaging to prepare the surgeon for proper margin attainment. E-cadherin, a negative membrane marker for lobular neoplasia, is useful in the distinction of lobular versus ductal neoplasia, but as a negative marker, can be difficult to interpret in particularly challenging cases. In this study, we surveyed primary and metastatic ductal lesions (62) and lobular lesions (64) of the breast to determine if P120 catenin is useful in the diagnostic distinction between lobular and ductal neoplasia. Primary breast ductal and lobular preneoplastic and neoplastic lesions were immunostained with E-cadherin and P120ctn and independently classified as ductal or lobular lesions. In addition, a wide array of carcinomas of different types were surveyed with P120ctn in tissue microarrays to ascertain whether the cytoplasmic P120ctn immunostaining pattern observed in lobular neoplasia was unique. Accurate categorization of ductal versus lobular neoplasia in the breast with P120ctn immunostaining was effective in all cases. Separation of low-grade ductal carcinoma in situ from lobular neoplasia was efficient. Diagnostically, P120ctn was particularly useful in identifying early lesions of lobular neoplasia. Of the other tumors that may morphologically mimic lobular carcinoma, only the diffusely infiltrating variants of rectal and gastric carcinomas showed diffuse cytoplasmic P120ctn immunostaining. Caution should be exercised when examining tumors in metastatic sites with P120ctn, with the incorporation of an appropriate panel of immunostains.
 ...
PMID:Lobular versus ductal breast neoplasms: the diagnostic utility of p120 catenin. 1732 85

P120-catenin plays an important role in cell adhesion and signalling transduction though the function of its isoforms is unclear. The aim of this study was to examine the expression of p120-catenin isoforms in lung cancer and investigate their relationship to clinicopathological factors in lung squamous cell carcinomas (SCCs) and adenocarcinomas. The expression patterns of p120-catenin in lung cancer tissues and lung cancer cells were examined by p120-catenin immunofluorescence, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Clear and continuous red fluorescence of p120-catenin is displayed at the cell membrane of corresponding normal bronchial epithelial cells, but not in lung cancer tissues that show reduction or absence of membrane expression of p120-catenin or cytoplasmic accumulation of p120-catenin. Compared with corresponding normal lung tissues, lung cancer tissues have significantly lower levels of p120-catenin proteins (P<0.001) and mRNA (P<0.001). The isoforms 1 (120 kD) and 3 (100 kD) proteins were major isoforms of p120-catenin expressed in normal lung tissues, which were significantly reduced in lung cancer samples (P=0.001 and P<0.001, respectively). The mRNA of p120-catenin isoforms 1.2, 1.3, 2.3, 3.1 and 3.3 was detected in corresponding normal lung tissues, but was significantly absent in lung cancer samples (P<0.001 and P=0.001, respectively). Furthermore, p120-catenin isoform 1 is negatively associated--whereas p120-catenin isoform 3 is positively associated--with lymph node metastasis. We conclude that reductions of isoforms 1 and 3 may play different roles in metastatic progression of human lung cancer.
 ...
PMID:Reduction of p120(ctn) isoforms 1 and 3 is significantly associated with metastatic progression of human lung cancer. 1761 52

Pleomorphic lobular carcinoma of the breast is a high nuclear grade variant of lobular carcinoma. E-cadherin, a tumor-invasion suppressor gene, codes for a transmembrane protein that functions in intercellular adhesion. The E-cadherin protein internal domain binds with alpha, beta, gamma, and p120 catenins to anchor the E-cadherin complex to the actin cytoskeleton of the cell. The E-cadherin gene is routinely mutated in lobular neoplasia. This study examines the morphomolecular spectrum of the components of the E-cadherin-catenin complex in lobular neoplasia. Fifteen cases of pleomorphic lobular neoplasia, 8 cases of classic lobular neoplasia and 4 ductal carcinomas were studied. Normal breast epithelium and invasive ductal carcinomas all showed intense linear cell membrane immunostaining with antibodies to E-cadherin, alpha, beta, gamma, and P120 catenins. Membrane immunostaining of the catenin antibodies in lobular neoplasia was negative, except for rare cases that displayed beaded or dotlike patterns. Cytoplasmic immunostaining patterns for all lobular lesions included coarse paranuclear granules of beta catenin or diffuse intense cytoplasmic staining for P120 catenin. These immunostaining patterns demonstrate that catenins alpha, beta, gamma, and p120 are routinely dislocated from the cell membrane into the cytoplasm in lobular neoplasia and that the disrupted catenin patterns parallel absence of membrane E-cadherin in all cases. The diffuse cytoplasmic immunostaining of p120 in lobular neoplasia may be useful diagnostically as a positive marker for lobular neoplasia.
 ...
PMID:The spectrum of morphomolecular abnormalities of the E-cadherin/catenin complex in pleomorphic lobular carcinoma of the breast. 1772 Dec 69

The mechanisms mediating and regulating assembly and disassembly of intercellular junctions is a subject of intensive research. The IgG autoantibodies produced in patients with the immunoblistering skin disease pemphigus vulgaris (PV) can induce keratinocyte (KC) dyshesion (acantholysis) via mechanisms that involve signaling kinases targeting intercellular adhesion molecules, thus providing a useful model to study the physiologic regulation of KC cohesion. Previous studies showed that activation of Src and protein kinase C are the earliest events in the PV IgG-induced intracellular phosphorylation cascades and that cholinergic agonists are effective for treating patients with pemphigus. In this study, we sought to elucidate the molecular mechanisms allowing cholinergic agonists to inhibit PV IgG-induced acantholysis and phosphorylation of KC adhesion molecules. The extent of acantholysis in KC monolayers correlated closely with the degree of PV IgG-induced phosphorylation of p120- and beta-catenins, with classic isoforms of protein kinase C mediating serine phosphorylation of beta-catenin and Src-tyrosine phosphorylation of p120-catenin. The M(1) muscarinic agonist pilocarpine blocked phosphorylation of both catenins, which could be abolised by the M(1) antagonist MT7. The alpha7 nicotinic agonist AR-R17779 inhibited phosphorylation of P120-cateinin. The alpha7 antagonist methyllycaconitine abolished the effect of AR-R17779. Okadaic acid abrogated protective effects of agonists on phosphorylation of beta-catenin, and pervanadate, on that of p120-catenin. Stimulation of KCs with pilocarpine significantly (p < 0.05) elevated both serine/threonine and tyrosine phosphatase activities in KCs. AR-R17779 both stimulated tyrosine phosphatase and decreased PV IgG-induced Src activity. Methyllycaconitine released Src activity in intact KCs and caused acantholysis. Thus, downstream signaling from M(1) abolished PV IgG-dependent catenin phosphorylation due to activation of both serine/threonine and tyrosine phosphatases, whereas alpha7 action involved both activation of tyrosine phosphatase and inhibition of Src. These findings identified novel paradigm of regulation of signaling kinases associated with cholinergic receptors and provided mechanistic explanation of therapeutic activity of cholinomimetics in PV patients.
 ...
PMID:Differential coupling of M1 muscarinic and alpha7 nicotinic receptors to inhibition of pemphigus acantholysis. 1807 10

P120 plays an essential role in cadherin turnover. The molecular mechanism involved, however, remains only partially understood. Here, using a gene trap targeting technique, we replaced the genomic sequence of p120 with HA-tagged p120 cDNA in mouse teratocarcinoma F9 cells. In the p120 knock-in (p120KI) cells, we found that the expression level of p120 was severely reduced and that the expression level of other components of the cadherin-catenin complex was also reduced. The stable expression of various p120 mutants in p120KI cells revealed that the armadillo repeat domain of p120 is sufficient to restore the expression level of E-cadherin. In p120KI cells, internalized E-cadherin was frequently detected as large aggregates. Transient expression of wild-type p120 and mutant p120 lacking the N-terminal region induced both relocalization of E-cadherin at the cell-cell boundaries and the disappearance of cytoplasmic E-cadherin aggregates. Transient expression of mutant p120 lacking the C-terminal region, however, only induced a small increase in E-cadherin signals at the cell-cell boundary. In these cells, the cytoplasmic E-cadherin signals became brighter and the expressed mutant p120 was incorporated in the E-cadherin aggregates. These results suggested the novel function of the p120 C-terminal region in regulating the trafficking of cytoplasmic E-cadherin.
 ...
PMID:Involvement of p120 carboxy-terminal domain in cadherin trafficking. 1815 25

P120-catenin (p120ctn) is an armadillo-repeat protein that directly binds to the intracytoplasmic domains of classical cadherins. p120ctn binding promotes the stabilization of cadherin complexes on the plasma membrane and thus positively regulates the adhesive activity of cadherins. Using co-immunoprecipitation, we show here that p120ctn associates to desmogleins (Dsg) 1 and 3. To determine which region is involved in the association between Dsg3 and p120ctn, we constructed mutant Dsg3 proteins, in which various cytoplasmic subdomains were removed. The tailless Dsg3 constructs Delta IA:AA1-641Dsg3 and Delta 641-714Dsg3, which do not contain the intracellular anchor (IA) region, did not coprecipitate with p120cn, nor did they colocalize at the plasma membrane. Immunocytochemical analysis revealed that p120ctn does not localize to desmosomes, but colocalizes with Dsg3 at the cell surface. A biotinylation assay for Dsg3 showed that biotinylated Delta 641-714Dsg3 was turned over more rapidly than wild-type Dsg3. These results indicate that the membrane proximal region (corresponding to residues 641-714) in the IA region of Dsg3 is necessary for complex formation with p120ctn, and to maintain free Dsg3 at the cell surface before it is integrated into desmosomes. In summary, we show that p120ctn is a novel interactor of the Dsg proteins, and may play a role in desmosome remodeling.
 ...
PMID:P120-catenin is a novel desmoglein 3 interacting partner: identification of the p120-catenin association site of desmoglein 3. 1834 67

Pleomorphic lobular carcinoma in situ (PLCIS) is a more recently characterized entity that mimics high-grade ductal carcinoma in situ (DCIS). PLCIS is sometimes treated similar to high-grade DCIS, but no consensus has been reached for the most appropriate treatment. The aim of this study is to evaluate the histologic and immunohistologic profile of pure PLCIS on core needle biopsies and present follow-up clinical data. We reviewed 12 cases of pure PLCIS diagnosed on core needle biopsies of the breast along with subsequent surgical resections. Histologically, all cases showed dyscohesive cells with grade 3 nuclei, prominent nucleoli, and moderate to abundant eosinophilic cytoplasm. A panel of immunohistochemical stains to study this entity included E-cadherin, P120 catenin, estrogen receptor, progesterone receptors, HER2/neu, and Ki-67 (MIB-1). Residual PLCIS was found on excisional biopsies in 83% (10/12) cases. Invasive lobular carcinoma was found in 25% (3/12) cases. The lobular nature of all cases was confirmed by negative E-cadherin and cytoplasmic-dominant staining with P120 catenin. PLCIS was positive for estrogen receptor in 92% (11/12); progesterone receptor in 50% (6/12), and Her2/neu was positive in 25% (3/12). A moderate to high proliferation activity was observed with MIB (Ki-67) staining in 92% (11/12) cases. We conclude that PLCIS has a lobular immunostaining pattern for P120 catenin and E-cadherin indicating disruption of the E-cadherin/P120 catenin complex. This entity has aggressive parameters similar to high-grade DCIS including grade 3 nuclei, high Ki-67 (MIB-1) index, and HER2/neu positivity. PLCIS has a significant association with other high-risk lesions and invasive lobular carcinoma.
 ...
PMID:Pleomorphic lobular carcinoma in situ (PLCIS) on breast core needle biopsies: clinical significance and immunoprofile. 1876 31


1 2 3 4 Next >>