Disease relevance of CNTNAP1

• Since no disease causing mutations were found, we suggest that Caspr1 is probably not a common cause of inherited peripheral neuropathies [1].
• RNA interference-mediated knockdown of neither p190 protein results in significant inhibition of neurite outgrowth in neuroblastoma cells, despite an apparent increase in RhoA activity [2].
• We analysed by immunohistochemistry on free-floating sections from multiple sclerosis brains the expression and distribution of nodal (Na(v) channels), paranodal (paranodin/Caspr) and juxtaparanodal (K(v) channels and Caspr2) molecules in demyelinated and remyelinated lesions [3].
• A deregulated p210 tyrosine kinase is found in chronic myelogenous leukemia, while a p190 form predominates in Ph+ ALL [4].
• We have also succeeded in cloning part of the gene for p190 and expressing it in Escherichia coli [5].

High impact information on CNTNAP1

• From its novel two-chain structure, we deduced that p190 was the prototype of a new class of tyrosine kinase receptors [6].
• We also show that the high level of p190 found in the GTL-16 cell line is accompanied by amplification and overexpression of c-met [6].
• Our evidence indicates that purified p190 can alter the course of parasitaemia in monkeys with falciparum malaria [5].
• P190 BCR/ABL induced lymphoid leukemia with shorter latency than P210 or P230 [7].
• Paranodin/contactin-associated protein (caspr) is a transmembrane glycoprotein of the neurexin superfamily that is highly enriched in the paranodal regions of myelinated axons [8].

Chemical compound and disease context of CNTNAP1

• Resistance to imatinib of bcr/abl p190 lymphoblastic leukemia cells [9].
• In addition to the previously reported P210 and P190 abl-related proteins, a novel Mr 53,000 protein was found to undergo phosphorylation at serine and tyrosine in immune complex kinase assays of two blast crisis CML cell lines (K562 and EM2) and in samples from blast crisis patients in which P210bcr-abl was detected [10].
• Treatment of P190 Bcr/Abl lymphoblastic leukemia cells with inhibitors of the serine/threonine kinase CK2 [11].
• AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells [12].
• One protein designated P190 has been found to be overexpressed in cell lines of human promyelocytic leukemia, lung and adenocarcinoma treated with adriamycin [13].

Biological context of CNTNAP1

• In this study, we physically mapped the Caspr1 gene on chromosome 17q21.1 and determined its genomic structure [1].
• We found that activation of v-Src induced association of tyrosine phosphorylated p190 with p120(RasGAP) and stimulation of p120(RasGAP)-associated RhoGAP activity, although p120(RasGAP) itself was not a target for phosphorylation by v-Src in chicken embryo cells [14].
• Regulation of RhoA GTP hydrolysis by the GTPase-activating proteins p190, p50RhoGAP, Bcr, and 3BP-1 [15].
• We now show that p190 is indistinguishable from the protein encoded by the c-met proto-oncogene and that the alpha beta-subunit structure is conserved in other human cell lines [6].
• Ph(+) ALL cells harbor a bcrabl fusion gene (e1a2) encoding a 190-kDa fusion protein (p190) involved in disease pathogenesis [16].

Anatomical context of CNTNAP1

• Since molecular alterations in septate-like junctions at the paranodes might have important consequences for the function of the nerve fiber, we considered that Caspr1 could be involved in the pathogenesis of inherited peripheral neuropathies [1].
• Furthermore, these effects were rapidly reversible since switching off v-Src led to dissociation of the p190/p120(RasGAP) complex, inactivation of p120(RasGAP)-associated RhoGAP activity and re-induction of actin stress fibres [14].
• NF-Fc significantly inhibited nodal clustering of Na(+) channels, ankyrin(G), and betaIV spectrin, and modestly reduced Caspr clustering at paranodal junctions; it did not significantly affect lengths or numbers of myelin-positive segments, axon initial segments, or accumulations of phosphorylated-ERM proteins in Schwann cell nodal microvilli [17].
• In both peripheral and central nervous systems, some paranodal loops failed to attach to the axolemma, and immunostaining of Caspr and NF155 was attenuated [18].
• Changes occurring in the transition from the soluble to membrane-bound state of the C-terminal 190-residue channel polypeptide of colicin E1 (P190) bound to anionic membranes are described [19].

Associations of CNTNAP1 with chemical compounds

• Under conditions of estradiol-dependent growth, estradiol treatment of human mammary cancer MCF-7 cells triggers rapid and transient activation of the mitogen-activated (MAP) kinases, erk-1 and erk-2, increases the active form of p21ras, tyrosine phosphorylation of Shc and p190 protein and induces association of p190 to p21ras-GAP [20].
• In this report, we demonstrate that RA-induced CD38 protein from human myeloid (HL-60) leukemia cells coimmunoprecipitates with another protein of molecular mass approximately190 kDa (p190) [21].
• Inhibition by p190 was prevented by GTP gamma S, a nonhydrolyzable analogue of GTP [22].
• We suggest that activation of the alpha6beta1 integrin signaling regulates the tyrosine phosphorylation state of p190 which in turn connects downstream signaling pathways through Rho family GTPases to actin cytoskeleton in invadopodia, thus promoting membrane-protrusive and degradative activities necessary for cell invasion [23].
• To characterize the p120.p190 interaction further, we used bacterially expressed glutathione S-transferase fusion polypeptides to map the regions of p120 necessary for its interactions with p190 [24].

Other interactions of CNTNAP1

• The catalytic efficiencies (Kcat/Km) of the GAP domains of Bcr, 3BP-1, and p190 on Cdc42 are found to be 60-, 160-, and over 500-fold less than that of Cdc42GAP, respectively, and the differences are due, to a large part, to differences in Km [25].
• p120GAP forms distinct complexes with two phosphoproteins, p62 and p190 [26].
• Partial sequence analysis of rhoGAP has led to the identification of a family of related proteins which now includes bcr, chimaerin, p190, p85, and 3BP-1 [27].
• The MRD1 (P-glycoprotein) and MRP (P-190) transporters do not play a major role in the intrinsic multiple drug resistance of Jurkat T lymphocytes [28].
• Follow up of patient 1 showed a progressive increase in WT-1 and in p-190 transcript, which was followed by cytogenetic and hematological relapse [29].

Analytical, diagnostic and therapeutic context of CNTNAP1

• In cells from 24 leukemias, single bcr-abl PCR products were detected that corresponded to breakpoints in the minor breakpoint cluster region (mbcr in intron 1 of the bcr gene) associated with production of the P190 fusion protein [30].
• Moreover, using a novel and very sensitive Western blot technique, we detected relevant amounts of P190 protein in addition to P210 from peripheral cells of two of the patients [31].
• BCR-ABL RT-PCR is confirmed as a sensitive, rapid method to diagnose t(9;22), and p190 and p210 are unequivocally demonstrated as the most important predictors of poor long-term survival despite intensified chemotherapy [32].
• By immunoprecipitation of surface-labeled CD45 molecules from MN thymocytes, a proportion of the CD45 is in fact of low molecular mass but does not include epitopes recognized by CD45R0, nor by CD45RB mAb specific for the p190 [33].
• In addition, the localized matrix degradation and membrane-protrusive activities were blocked by treatment of LOX cells with tyrosine kinase inhibitors as well as microinjection of antibodies directed against p190 but not by non-perturbing antibodies or control buffers [23].

References