Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1

Abstract

In addition to acting as a transcriptional co-activator, YAP1 directly mediates translocalization of the pro-oncogenic phosphatase SHP2 from the cytoplasm to nucleus. In the cytoplasm, SHP2 potentiates RAS–ERK signaling, which promotes cell proliferation and cell motility, whereas in the nucleus, it mediates gene regulation. As a result, elucidating the details of SHP2 trafficking is important for understanding its biological roles, including in cancer. YAP1 comprises multiple splicing isoforms defined in part by the presence (as in YAP1-2γ) or absence (as in YAP1-2α) of a γ-segment encoded by exon 6 that disrupts a critical leucine zipper. Although the disruptive segment is known to reduce co-activator function, it is unclear how this element impacts the physical and functional relationships between YAP1 and SHP2. To explore this question, we first demonstrated that YAP1-2γ cannot bind SHP2. Nevertheless, YAP1-2γ exhibits stronger mitogenic and motogenic activities than does YAP1-2α because the YAP1-2α–mediated delivery of SHP2 to the nucleus weakens cytoplasmic RAS–ERK signaling. However, YAP1-2γ confers less in vivo tumorigenicity than does YA1-2α by recruiting tumor-inhibitory macrophages. Mechanistically, YAP1-2γ transactivates and the YAP1-2α–SHP2 complex transrepresses the monocyte/macrophage chemoattractant CCL2. Thus, cell-intrinsic and cell-extrinsic pro-oncogenic YAP1 activities are inversely regulated by alternative splicing of exon 6. Notably, oncogenic KRAS down-regulates the SRSF3 splicing factor that prevents exon 6 skipping, thereby creating a YAP1-2α–dominant situation that supports a “cold” immune microenvironment. In addition to acting as a transcriptional co-activator, YAP1 directly mediates translocalization of the pro-oncogenic phosphatase SHP2 from the cytoplasm to nucleus. In the cytoplasm, SHP2 potentiates RAS–ERK signaling, which promotes cell proliferation and cell motility, whereas in the nucleus, it mediates gene regulation. As a result, elucidating the details of SHP2 trafficking is important for understanding its biological roles, including in cancer. YAP1 comprises multiple splicing isoforms defined in part by the presence (as in YAP1-2γ) or absence (as in YAP1-2α) of a γ-segment encoded by exon 6 that disrupts a critical leucine zipper. Although the disruptive segment is known to reduce co-activator function, it is unclear how this element impacts the physical and functional relationships between YAP1 and SHP2. To explore this question, we first demonstrated that YAP1-2γ cannot bind SHP2. Nevertheless, YAP1-2γ exhibits stronger mitogenic and motogenic activities than does YAP1-2α because the YAP1-2α–mediated delivery of SHP2 to the nucleus weakens cytoplasmic RAS–ERK signaling. However, YAP1-2γ confers less in vivo tumorigenicity than does YA1-2α by recruiting tumor-inhibitory macrophages. Mechanistically, YAP1-2γ transactivates and the YAP1-2α–SHP2 complex transrepresses the monocyte/macrophage chemoattractant CCL2. Thus, cell-intrinsic and cell-extrinsic pro-oncogenic YAP1 activities are inversely regulated by alternative splicing of exon 6. Notably, oncogenic KRAS down-regulates the SRSF3 splicing factor that prevents exon 6 skipping, thereby creating a YAP1-2α–dominant situation that supports a “cold” immune microenvironment. YAP1 (yes-associated protein 1, and its paralog TAZ) is a transcriptional co-activator that interacts with a number of sequence-specific transcription factors, most notably TEADs, and thereby transactivates downstream target genes, which stimulates cell proliferation while preventing cell death (1Zhao B. Wei X. Li W. Udan R.S. Yang Q. Kim J. Xie J. Ikenoue T. Yu J. Li L. Zheng P. Ye K. Chinnaiyan A. Halder G. Lai Z.C. et al.Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.Genes Dev. 2007; 21 (17974916): 2747-276110.1101/gad.1602907Crossref PubMed Scopus (1767) Google Scholar). Accordingly, YAP1 is considered to be a pro-oncogenic co-activator, deregulation of which promotes the development of cancer (2Zanconato F. Cordenonsi M. Piccolo S. YAP/TAZ at the roots of cancer.Cancer Cell. 2016; 29 (27300434): 783-80310.1016/j.ccell.2016.05.005Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar). YAP1 shuttles between the cytoplasm and nucleus in response to various signals including the Hippo signal, which plays an important role in restricting organ size by controlling cell proliferation and apoptosis (3Pan D. Hippo signaling in organ size control.Genes Dev. 2007; 21 (17437995): 886-89710.1101/gad.1536007Crossref PubMed Scopus (476) Google Scholar). The Hippo pathway contains two core serine/threonine kinases: MST and LATS. When the Hippo signal is off, nonphosphorylated YAP1 enters the nucleus, where it acts as a transcriptional co-activator by binding with TEADs (4Ota M. Sasaki H. Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling.Development. 2008; 135 (19004856): 4059-406910.1242/dev.027151Crossref PubMed Scopus (274) Google Scholar, 5Zhao B. Ye X. Yu J. Li L. Li W. Li S. Yu J. Lin J.D. Wang C.Y. Chinnaiyan A.M. Lai Z.C. Guan K.L. TEAD mediates YAP-dependent gene induction and growth control.Genes Dev. 2008; 22 (18579750): 1962-197110.1101/gad.1664408Crossref PubMed Scopus (1408) Google Scholar). When the Hippo signal is on, however, MST-activated LATS phosphorylates cytoplasmic YAP1 to prevent its nuclear translocalization (6Meng Z. Moroishi T. Guan K.L. Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30 (26728553): 1-1710.1101/gad.274027.115Crossref PubMed Scopus (688) Google Scholar). Thus, impaired Hippo signaling also contributes to neoplastic transformation of cells by deregulating YAP1 (7Park H.W. Guan K.L. Regulation of the Hippo pathway and implications for anticancer drug development.Trends Pharmacol. Sci. 2013; 34 (24051213): 581-58910.1016/j.tips.2013.08.006Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). The YAP1 gene comprises nine exons and generates at least eight differentially spliced YAP1 isoforms (YAP1-1α, YAP1-1β, YAP1-1γ, YAP1-1δ, YAP1-2α, YAP1-2β, YAP1-2γ, and YAP1-2δ) (Fig. 1A) (8Gaffney C.J. Oka T. Mazack V. Hilman D. Gat U. Muramatsu T. Inazawa J. Golden A. Carey D.J. Farooq A. Tromp G. Sudol M. Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of YAP1 PubMed Scopus Google Scholar, M. YAP1 and its eight 2013; PubMed Scopus Google Scholar). and isoforms are by and of exon which the of exon which the γ-segment a to which are by the presence of a functional leucine that of exon 6 in the of which a leucine because of of the an alternative in a exon a which also disrupts the leucine Thus, exon generates and isoforms in the absence and presence of exon (Fig. 1A) (8Gaffney C.J. Oka T. Mazack V. Hilman D. Gat U. Muramatsu T. Inazawa J. Golden A. Carey D.J. Farooq A. Tromp G. Sudol M. Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of YAP1 PubMed Scopus Google Scholar, M. YAP1 and its eight 2013; PubMed Scopus Google Scholar). YAP isoforms two stronger co-activator than a A. M. Sudol M. protein YAP with and acts as a for the of that to the Full Text Full Text PDF PubMed Scopus Google Scholar). YAP1 isoforms the leucine a co-activator in the 2016; 6 Google Scholar). YAP1 YAP1-2α and YAP1-2γ are two YAP1 splicing isoforms that to the and of of A. M. Sudol M. protein YAP with and acts as a for the of that to the Full Text Full Text PDF PubMed Scopus Google Scholar, M. protein is a that to the of the Google Scholar). In to the presence of multiple splicing isoforms of encoded by the is a in in a of X. phosphatase in and PubMed Google Scholar). of SHP2 by the oncoprotein also plays an important role in the development of cancer M. and a for Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, SHP2 is as a pro-oncogenic In the cytoplasm, SHP2 potentiates the of RAS–ERK signaling G. D. The phosphatase in cancer.Cancer 2008; PubMed Scopus Google Scholar, M. A. A. P. The of in the protein 2008; PubMed Scopus Google and that the growth of cancer cells oncogenic KRAS is SHP2 J. A. D. K. Z. M. L. et PubMed Scopus Google Scholar). SHP2 is in the cytoplasm at a cell is in the nucleus at a cell The cell of SHP2 is regulated by the of SHP2 with in which YAP1 acts as a and SHP2 as a M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). also that of interacts with the of to as with the of to as isoforms are by is considered to be regulated by alternative splicing of YAP1 mRNA M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google that splicing the co-activator also the of In the we YAP1-2α and YAP1-2γ as isoforms that an leucine and a leucine to cell-intrinsic and cell-extrinsic pro-oncogenic activities are between the two YAP1 by the in of exon 6 YAP1 is by the SRSF3 and splicing factor splicing the of which is by oncogenic The a between differentially spliced YAP1 isoforms and SHP2 in the of and YAP1 of which contributes to the of a microenvironment. To splicing of YAP1 M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google SHP2 with of the YAP1 splicing isoforms in that SHP2 most with YAP1-2α and with and also SHP2 less the of the and isoforms of which the with SHP2 (Fig. a critical role of the leucine in the that the γ-segment is and thereby disrupts the leucine in YAP1 (Fig. 1A) (8Gaffney C.J. Oka T. Mazack V. Hilman D. Gat U. Muramatsu T. Inazawa J. Golden A. Carey D.J. Farooq A. Tromp G. Sudol M. Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of YAP1 PubMed Scopus Google the the of the leucine in SHP2 To this a leucine of YAP1-2α in which of and by with SHP2 in In to YAP1-2α, to with SHP2 (Fig. leucine which comprises a interacts with leucine T. of the leucine Dev. PubMed Scopus Google Scholar). SHP2 does a leucine YAP1 to bind SHP2 directly the leucine zipper. In this the YAP a functional leucine which is involved in YAP1 binding M. M. protein is a critical for a transcription factor in Sci. PubMed Scopus Google Scholar). To YAP1-2α with YAP1-2α, YAP1-2γ, or in YAP1-2α a complex with YAP1-2α or in the cells (Fig. of YAP1-2α or and or a in which of and by in cells or (Fig. YAP1-2α and leucine Notably, YAP1-2β, by of the the leucine of YAP1-2α, the of YAP1 to with (Fig. The also by the of leucine (Fig. and of in cells by and YAP1-2α–SHP2 complex (Fig. and that binding of YAP1 with SHP2 between YAP1 and As to the nucleus and cytoplasm at a cell whereas it from the nucleus at a cell M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). regulated by splicing of YAP1 nuclear translocalization of SHP2 considered to be by YAP1 isoforms of binding with SHP2. To this YAP1 and of which are to the nucleus of cell X. mediates contact inhibition of proliferation Hippo PubMed Scopus Google in cancer cells and in in a As a result, and in the nucleus (Fig. the to the cytoplasm in cells in the nucleus (Fig. Accordingly, of SHP2 by the of the YAP1 SHP2 and YAP1 are known to be cell as as cell (1Zhao B. Wei X. Li W. Udan R.S. Yang Q. Kim J. Xie J. Ikenoue T. Yu J. Li L. Zheng P. Ye K. Chinnaiyan A. Halder G. Lai Z.C. et al.Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.Genes Dev. 2007; 21 (17974916): 2747-276110.1101/gad.1602907Crossref PubMed Scopus (1767) Google Scholar, G. D. The phosphatase in cancer.Cancer 2008; PubMed Scopus Google Scholar). the pro-oncogenic of YAP1-2α and To this we two cell from cells and two (Fig. the of SHP2 in cells by YAP1 in cells as (Fig. T. H.W. B. Q. Z. K. Yu M. D. Guan K.L. Hippo pathway Dev. 29 PubMed Scopus Google Scholar). for YAP1-2α or YAP1-2γ or cells to that of the two YAP1 to as and cells (Fig. or and cells (Fig. at In or SHP2 to the cytoplasm at a cell because of the of with YAP1 (Fig. the SHP2 in the nucleus of cells at a cell because of the complex (Fig. with the that YAP1 is growth of or cells with that of and the growth by YAP1-2α or YAP1-2γ in or cells (Fig. and Notably, or cells with YAP1-2γ than or cells with YAP1-2α (Fig. and a or that YAP1-2α exhibits stronger transcriptional co-activator TEAD than YAP1-2γ does as (Fig. A. M. Sudol M. protein YAP with and acts as a for the of that to the Full Text Full Text PDF PubMed Scopus Google Scholar, in the 2016; 6 Google the in growth be by co-activator cytoplasmic SHP2 is involved in of the RAS–ERK signaling pathway M. A. A. P. The of in the protein 2008; PubMed Scopus Google Scholar, T. H. H. phosphatase a that promotes Sci. PubMed Scopus Google a in the of cytoplasmic SHP2 by YAP1-2α to be involved in the mitogenic of YAP1-2α with that of In the of RAS–ERK signal by the of in or cells in cells with that in cells (Fig. As in the of of in cells by to an in the of cytoplasmic at a cell (Fig. which with the in the of (Fig. To this SHP2 or an SHP2 that cannot bind YAP1 and is in the cytoplasm M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google or The cell growth that of to a in cell growth (Fig. and also to the of YAP1-2α and YAP1-2γ cell L. S. Z. X. S. Yang A. W. Q. of YAP and is an of in cancer and to the proliferation and of cancer 2013; PubMed Scopus Google Scholar, H. A. Li P. B. X. Z. Z. Zheng M. and by YAP in cancer 2013; PubMed Scopus Google Scholar). YAP1-2α and YAP1-2γ the of and the motogenic of YAP1-2γ stronger than that of YAP1-2α (Fig. to the oncogenic of the YAP1 splicing isoforms in a to YAP1 isoforms are of the neoplastic of cells in B. Ye X. Yu J. Li L. Li W. Li S. Yu J. Lin J.D. Wang C.Y. Chinnaiyan A.M. Lai Z.C. Guan K.L. TEAD mediates YAP-dependent gene induction and growth control.Genes Dev. 2008; 22 (18579750): 1962-197110.1101/gad.1664408Crossref PubMed Scopus (1408) Google Scholar, P. H. M. that the pathway and cell PubMed Scopus Google To cells with a YAP1-2α or YAP1-2γ and to a by and a with by cells In with by cells YAP1-2γ (Fig. The of YAP1-2α by (Fig. that cytoplasmic SHP2 is with the of we that YAP1-2γ in pro-oncogenic activities than YAP1-2α most by the between YAP1-2α and To the in that YAP1-2γ is oncogenic than YAP1-2α in an in vivo a in cells are in and to in vivo oncogenic of of the signaling To this of that of YAP1-2α or YAP1-2γ, as by the (Fig. of the with the of whereas of cells in that YAP1-2α and YAP1-2γ in vivo tumorigenicity In to the in in however, the of the by YAP1-2α than by YAP1-2γ in (Fig. of and (Fig. To the for the in vivo with which in vivo A. of of of and PubMed Scopus Google Scholar). In with cells to with that with or than of from cells (Fig. and in by analysis (Fig. the in vivo of To the by which cells in from two of and and to analysis a S. A. in and cancer J. Sci. Scopus Google to differentially between the cell the for which the mRNA in cells than in cells and and the for which the mRNA in cells than in cells and by genes, the in in mRNA for in in a chemoattractant of and role of J. PubMed Scopus Google Scholar). In and cells to an in mRNA with that in cells YAP1-2α (Fig. and to be a transcriptional target of W. B. B. Yang Hippo signaling to PubMed Scopus Google Scholar, X. H. Yang S. X. X. F. Li L. X. T. J. L. et cells immune by recruiting Dev. PubMed Scopus Google Scholar). As in the 2016; 6 Google YAP1-2α in than YAP1-2γ (Fig. and YAP1-2α and the Tead target genes, than YAP1-2γ by analysis (Fig. In YAP1-2γ than YAP1-2α in (Fig. we that induction by binding of YAP1 with SHP2. of the leucine in YAP1-2α YAP1-2α from a to an of that SHP2 binding the co-activator of YAP1 (Fig. To the cells by the the of and protein (Fig. it a in the of mRNA (Fig. of SHP2 cell growth also the mRNA to the (Fig. Although the the to which cannot bind to (Fig. that YAP1-2α–SHP2 complex SHP2 phosphatase is for the of SHP2. The for the role of in TEAD transcription and bind to the element binding factor is to the binding Full Text PDF PubMed Google Scholar). element between and of the transcription of the which also in the (Fig. To is with the element in a an The a for the (Fig. with Tead in cells in the presence of the complex (Fig. with in cells in the presence of the complex (Fig. we by with various of the The cells and As a result, the of the that of the or by of SHP2 (Fig. the presence of an element between and of the in which the element also of the with YAP1-2α, YAP1-2γ or a cells that the by YAP1-2α by YAP1-2γ (Fig. and SHP2 the than which cannot bind YAP1 (Fig. of YAP1-2α the in cells (Fig. in this YAP1-2α in a from a from the to a co-activator from the the as the with YAP1-2γ in Accordingly, which cannot bind whereas transcription YAP1-2α a complex with SHP2. To the the alternative splicing of exon 6 in YAP1 we for splicing in YAP1 exon 6 the F. M. L. G. a of target by splicing proteins in PubMed Scopus Google and we SRSF3 binding in the (Fig. To the of exon 6 in YAP1 a the exon YAP1 isoforms by (Fig. which a encoded by exon and exon also to the YAP mRNA (Fig. To involved in the exon 6 splicing of YAP1 cells (Fig. or cells (Fig. by the The of exon 6 in this cells (Fig. and Notably, the of and protein in cells (Fig. involved in the of by mRNA in or cells by As a result, cells a of which and by of that SRSF3 and are at the (Fig. SRSF3 the growth of and cells (Fig. that splicing of YAP1 for the growth of of by YAP1-2α and YAP1-2γ also at the protein in the because by (Fig. of SRSF3 also in cells in cells (Fig. that mRNA by of exon 6 the of which acts as a co-activator of TEADs because of the of KRAS to nuclear translocalization of SHP2 A. A. M. T. M. M. SHP2 phosphatase from a to an oncogenic Cell. Full Text Full Text PDF PubMed Scopus Google the that it exon 6 in To this cells and of oncogenic KRAS (Fig. and analysis that of exon 6 in mRNA in cells of oncogenic KRAS (Fig. of also in cells oncogenic KRAS (Fig. As a result, oncogenic KRAS exon 6 in YAP1 by the protein with a or a the oncogenic in in cells (Fig. signal be involved at least in the of M. of the signaling pathway by the PubMed Scopus Google Scholar). KRAS is most in and J. C.J. the PubMed Scopus Google Scholar). analysis of the J. U. A. C.J. B. The cancer an for cancer PubMed Scopus Google Scholar, J. U. G. B. A. analysis of complex cancer and the 2013; 6 PubMed Scopus Google that of with a of SRSF3 to that of with SRSF3 for (Fig. The of with a of also to that of with a of for cancer (Fig. a between SRSF3 and in cancer (Fig. a between SHP2 and (Fig. in and cancer KRAS (Fig. also the of between KRAS and SRSF3 in YAP1 mRNA splicing that the of with KRAS YAP1-2α and YAP1-2γ are two isoforms of YAP1 that are by alternative splicing of exon which the γ-segment (8Gaffney C.J. Oka T. Mazack V. Hilman D. Gat U. Muramatsu T. Inazawa J. Golden A. Carey D.J. Farooq A. Tromp G. Sudol M. Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of YAP1 PubMed Scopus Google Scholar). of the γ-segment disrupts the leucine in Thus, YAP1-2α, exon a functional leucine whereas YAP1-2γ, exon does In the we that YAP1-2α interacts with SHP2 in a that the functional leucine zipper. also that YAP1-2α a with functional leucine with the of M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, X. mediates contact inhibition of proliferation Hippo PubMed Scopus Google that the of SHP2 with of two in YAP1-2α YAP1-2α and are with SHP2 with YAP1-2α is most because a complex and SHP2 as a and a that SHP2 is from the cytoplasm to the nucleus. The that YAP1-2γ stimulates cell proliferation and motility, as as growth of than YAP1-2α The is to binding of the YAP1 isoforms with SHP2. YAP1-2γ does bind YAP1-2γ does cytoplasmic SHP2 a and thereby potentiates RAS–ERK signaling that stimulates cell proliferation and cell YAP1-2γ confers cell-intrinsic pro-oncogenic cells than YAP1-2α In to in cells YAP1-2α are in vivo than are cells The oncogenic between YAP1-2α and YAP1-2γ in in vivo is to the in the of to the which is by the that cells the that to the Li J. H. T. J. to PubMed Scopus Google whereas cells Mechanistically, is by the complex W. B. B. Yang Hippo signaling to PubMed Scopus Google Scholar, X. H. Yang S. X. X. F. Li L. X. T. J. L. et cells immune by recruiting Dev. PubMed Scopus Google and we the in the in the transactivates by binding to the and transactivates in of tumor-inhibitory in the is from a to a binding of YAP1-2α with SHP2. The of in cells in that YAP1-2α and YAP1-2γ cell-extrinsic in a microenvironment. is that and biological activities of a to in The Hippo signal LATS acts as a by preventing nuclear translocalization of However, a that LATS in vivo T. T. J. Guan K.L. The Hippo pathway cancer 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). whereas of a tumor-inhibitory or a is by of multiple and H. K. that the PubMed Scopus Google Scholar). In that than X. H. Yang S. X. X. F. Li L. X. T. J. L. et cells immune by recruiting Dev. PubMed Scopus Google Scholar). splicing is by the which is of nuclear proteins and splicing factor which bind to and regulate the between and thereby or the of splicing in a of Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). also known as is the of the is in cell and to a role in the of alternative exon in a of genes, including as and S. F. an of its role in 2013; PubMed Scopus Google Scholar, L. and of splicing in PubMed Scopus Google and the YAP1 to this In the cells in YAP1 mRNA isoforms exon which with mRNA the role of the in the of SRSF3 is in various and considered to be pro-oncogenic L. and of splicing in PubMed Scopus Google Scholar). is with the of the that YAP1-2γ which is by exhibits cell-intrinsic pro-oncogenic YAP1 by SHP2 in the cytoplasm, which RAS–ERK signaling. however, oncogenic KRAS to SRSF3 a that is with the of YAP1 isoforms exon 6 exon 6 in cells oncogenic KRAS (Fig. that immune is for of oncogenic KRAS the of an “cold” in which cells by SHP2 H. W. J. Xie Zheng H. J. Yu S. G. X. phosphatase the and Full Text Full Text PDF PubMed Scopus Google Scholar). with of with of G. S. F. F. phosphatase in 2013; PubMed Scopus Google Scholar). of which to cancer Li S. J. F. T. B. V. Wang H. acts as a in Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The that SHP2 transcriptional of with YAP1 (Fig. The of cells for and be In the we that YAP1-2α YAP1-2γ to (Fig. also that YAP1-2α YAP1-2γ to (Fig. to YAP1-2α YAP1-2γ (Fig. In we demonstrated that cells two the and and that interacts with M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). also that with whereas of M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). that the does the analysis of of isoforms with and The also by the in YAP1 and and and and and SHP2 and and the leucine and between YAP1-2α and and the leucine of and are In the which the leucine are in YAP1 and Although the a of by of splicing isoforms of YAP1 than that of the the the first for the presence of in the of differentially spliced which are from by or splicing The the of alternative splicing in the biological of a gene Notably, in splicing in that splicing is also with K. M. D. A. A. M. G. M. T. et pathway of splicing in PubMed Scopus Google Scholar). In the of the between splicing isoforms with and exon 6 is important for the and of and YAP1 activities that in of The to the that of YAP1 splicing to the development of cancer a microenvironment. cells in with cells and cells in with The cells with to the the cells for In the cells at a cell or a cell The as for and and at 6 of for of the in cells for in at the of and cells of The at 6 or or a the the to the by the for at the of of the of cells for cells in of and the of and in a of a The cells for The with for at and a The YAP1 isoforms and two by and the by the or for SHP2 M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). The M. A. T. M. M. YAP and Hippo signaling as a for nuclear SHP2 Cell. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). The for and and the The SRSF3 the by the by the and the The is as and and cells The the and the of by the of The cells with in and for the cells with at a of The cells and with The cells with for by as by a or with and with for in in and The and with the to the The by of the to the by the for at the of of the of The cells and in the and the cell with with proteins or the with and protein The with and the immune complex with The proteins The to or The cells and for at The in a The of the cells at the of the at and the of the cells The by from cells or of for transcription with and the The as YAP1 exon and YAP1 and exon and and and and and The of to the transcription to as the and by The cells in and as a the cells with of a and for the cells and with for at by for The cells with and in The on, The at with an or an and to the of as and by the to with cancer and for and to L. G. the of PubMed Scopus Google to for between and the of and of biological are in the to The The to and The between the for the analysis of the by and for the of growth in vivo and from to the of the and the and to this are in the and the of the for and with with with regulated protein leucine protein transcriptional co-activator with mRNA nuclear protein

Topics & Concepts