細胞遷移無論在胚胎發育或是癌症轉移都扮演著關鍵的過程。但如何挑選上皮細胞並促使其開始進行移動的機制仍然不清楚。因此，本研究應用果蠅的邊境細胞 (Border cell) 作為研究集體細胞遷移的模型，邊境細胞是一小群從上皮脫離並通過果蠅卵子發生中的生殖細胞遷移的細胞。並且從遺傳篩選中發現 dysfusion (dysf) 的過度表達嚴重阻礙了Jak/Stat信號所控制的邊境細胞募集。相反地，dysf 突變的情況下會導致額外的邊境細胞開始遷移。此外，過度表現Dysf會影響 Stat蛋白的磷酸化、轉錄活性和核輸入(nuclear import)。而由過表達Jak/Stat 訊號所引起過多邊境細胞的表型可以通過同時過度表達Dysf來抑制，這也表明了 dysf 為Jak/Stat 信號傳導的負調節因子。而與之前的報導不同，本研究發現在果蠅的卵子生成時(oogenesis)，Dysf 蛋白存在於所有的生殖細胞和卵泡細胞核膜的內膜上(inner nuclear membrane)，但在邊境細胞開始遷移時期表現量會開始降低。此外，當邊境細胞到卵母細胞時，Dysf 蛋白訊號無法被檢測到。本研究透過生化篩選來尋找與內源性的Dysf相互作用的蛋白質來釐清Dysf如何調節Stat核轉運。並發現 Pendulin (Pen)是屬於Importin-alpha 蛋白家族的成員，它與 Dysf 相互作用來降低 Stat 蛋白的進核。此外，本研究也發現Dysfusion的同源蛋白-Npas4 也會負向調節 Stat3 和以及降低癌細胞遷移。因此，dysf 可以通過調節 Jak/Stat 信號來確定邊界細胞團的大小。

Cell migration is a critical process for embryonic development and cancer metastasis, but the epithelial cells are selected and adapt to migratory cell fate remains elusive. To understand the underlying mechanism, we apply border cells (BCs), a small group of cells disseminating from the epithelium and migrating through germ cells in Drosophila oogenesis, as a model to study collective cell movement. In a forward genetic screen, we find that overexpression of dysfusion (dysf) severely impedes BC recruitment which is governed by Jak/Stat signaling. Conversely, loss of dysf led to extra migratory BCs. It is noteworthy that Dysf gain of function dramatically impairs the phosphorylation, transcriptional activity, and nuclear import of Stat protein. The ectopic BC phenotype caused by Jak or Upd overexpression can be suppressed by overexpression of UAS-dysf, indicating that dysf negatively regulates Jak/Stat signaling. Furthermore, Dysf protein is located at the nuclear membrane of all germline and follicle cells but specifically reduced in BCs upon migration. Moreover, when BCs reach their destination, oocyte their Dysf becomes undetectable. Further research showed that Notch is upstream of Dysf to regulate its downregulation. To elucidate how Dysf regulates Stat nuclear transport, we carried out a biochemical screen to seek proteins interacting with endogenous knock-in tagged Dysf. We found that Dysf gates Stat nuclear imports by interacting with Pendulin, a member of the Importin-alpha protein family, and that mammalian homologue of Dysfusion (Npas4) negatively regulates the Stat3 and cancer cell migration. Therefore, dysf may determine the size of border cell clusters by regulating Jak/Stat signaling. Investigating the general role of dysf in Drosophila development that dysf affects both adult fly eye development and the formation of germline stem cells during oogenesis.

Adam, J.C., and Montell, D.J. (2004). A role for extra macrochaetae downstream of Notch in follicle cell differentiation. Development 131, 5971-5980.

Alexander, W.S., and Hilton, D.J. (2004). The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immuneresponse. Annu Rev Immunol 22, 503-529.
Aman, A., and Piotrowski, T. (2010). Cell migration during morphogenesis. Dev Biol 341, 20-33.

Asaoka, M., Hanyu-Nakamura, K., Nakamura, A., and Kobayashi, S. (2019). Maternal Nanos inhibits Importin-alpha2/Pendulin-dependent nuclear import to prevent somatic gene expression in the Drosophila germline. PLoS genetics 15, e1008090.

Atchley, W.R., and Fitch, W.M. (1997). A natural classification of the basic helix-loop-helix class of transcription factors. Proc Natl Acad Sci USA 94, 5172-5176.

Baade, I., Spillner, C., Schmitt, K., Valerius, O., and Kehlenbach, R.H. (2018). Extensive Identification and In-depth Validation of Importin 13 Cargoes. Mol Cell Proteomics 17, 1337-1353.

Bach, E.A., Ekas, L.A., Ayala-Camargo, A., Flaherty, M.S., Lee, H., Perrimon, N., and Baeg, G.H. (2007). GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. Gene expression patterns : GEP 7, 323-331.

Bai, J., Uehara, Y., and Montell, D.J. (2000). Regulation of invasive cell behavior by taiman, a Drosophila protein related to AIB1, a steroid receptor coactivator amplified in breast cancer. Cell 103, 1047-1058.

Bai, J.W., and Montell, D. (2002). Eyes Absent, a key repressor of polar cell fate during Drosophila oogenesis. Development 129, 5377-5388.

Bausek, N. (2013). JAK-STAT signaling in stem cells and their niches in Drosophila. Jak-Stat 2, e25686.

Best, B.T. (2019). Single-cell branching morphogenesis in the Drosophila trachea. Dev Biol 451, 5-15.
Bloodgood, B.L., Sharma, N., Browne, H.A., Trepman, A.Z., and Greenberg, M.E. (2013). The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 503, 121-125.

Borensztejn, A., Boissoneau, E., Fernandez, G., Agnes, F., and Pret, A.M. (2013). JAK/STAT autocontrol of ligand-producing cell number through apoptosis. Development 140, 195-204.

Bromberg, J. (2002). Stat proteins and oncogenesis. J Clin Invest 109, 1139-1142.

Bromberg, J.F., Wrzeszczynska, M.H., Devgan, G., Zhao, Y.X., Pestell, R.G., Albanese, C., and Darnell, J.E. (1999). Stat3 as an oncogene. Cell 98, 295-303.

Catlett-Falcone, R., Landowski, T.H., Oshiro, M.M., Turkson, J., Levitzki, A., Savino, R., Ciliberto, G., Moscinski, L., Fernandez-Luna, J.L., Nunez, G., et al. (1999). Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105-115.

Chen, D.Y., Crest, J., Streichan, S.J., and Bilder, D. (2019). Extracellular matrix stiffness cues junctional remodeling for 3D tissue elongation. Nat Commun 10.

Chen, M.Q., Sun, F., Han, L., and Qu, Z.X. (2016). Kaposi's sarcoma herpesvirus (KSHV) microRNA K12-1 functions as an oncogene by activating NF-kappa B/IL-6/STAT3 signaling. Oncotarget 7, 33363-33373.

Chen, S.Y., Wang, S., and Xie, T. (2011). Restricting self-renewal signals within the stem cell niche: multiple levels of control. Curr Opin Genet Dev 21, 684-689.

Conway, G., Margoliath, A., WongMadden, S., Roberts, R.J., and Gilbert, W. (1997). Jak1 kinase is required for cell migrations and anterior specification in zebrafish embryos. Proc Natl Acad Sci USA 94, 3082-3087.

Cordoba, S., and Estella, C. (2014). The bHLH-PAS transcription factor dysfusion regulates tarsal joint formation in response to Notch activity during drosophila leg development. PLoS genetics 10, e1004621.

Cordoba, S., and Estella, C. (2018). The transcription factor Dysfusion promotes fold and joint morphogenesis through regulation of Rho1. PLoS genetics 14, e1007584.

Croker, B.A., Kiu, H., and Nicholson, S.E. (2008). SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19, 414-422.

de Celis, J.F., Tyler, D.M., de Celis, J., and Bray, S.J. (1998). Notch signalling mediates segmentation of the Drosophila leg. Development 125, 4617-4626.

Decker, T. (1999). Introduction: STATs as essential intracellular mediators of cytokine responses. Cell Mol Life Sci 55, 1505-1508.

Devreotes, P., and Horwitz, A.R. (2015). Signaling Networks that Regulate Cell Migration. Cold Spring Harb Perspect Biol 7, a005959.

Dolezal, D., and Pignoni, F. (2015). BMP Signaling and Stem Cell Self-Renewal in the Drosophila Ovary. Principles of Developmental Genetics, 2nd Edition, 77-96.

Dona, E., Barry, J.D., Valentin, G., Quirin, C., Khmelinskii, A., Kunze, A., Durdu, S., Newton, L.R., Fernandez-Minan, A., Huber, W., et al. (2013). Directional tissue migration through a self-generated chemokine gradient. Nature 503, 285-289.

Duchek, P., Somogyi, K., Jekely, G., Beccari, S., and Rorth, P. (2001). Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 107, 17-26.

Ernst, S., and Muller-Newen, G. (2019). Nucleocytoplasmic Shuttling of STATs. A Target for Intervention? Cancers (Basel) 11,1815.

Fares, J., Fares, M.Y., Khachfe, H.H., Salhab, H.A., and Fares, Y. (2020). Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther 5.

Feldherr, C.M. (1985). The Uptake and Accumulation of Proteins by the Cell-Nucleus. Bioessays 3, 52-55.

Felix, M., Chayengia, M., Ghosh, R., Sharma, A., and Prasad, M. (2015). Pak3 regulates apical-basal polarity in migrating border cells during Drosophila oogenesis. Development 142, 3692-3703.

Friedl, P., and Gilmour, D. (2009). Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Bio 10, 445-457.

Fuller, M.T., and Spradling, A.C. (2007). Male and female Drosophila germline stem cells: Two versions of immortality. Science 316, 402-404.

Geisbrecht, E.R., Sawant, K., Su, Y., Liu, Z., Silver, D.L., Burtscher, A., Wang, X.J., Zhu, A.J., and McDonald, J.A. (2013). Genetic Interaction Screens Identify a Role for Hedgehog Signaling in Drosophila Border Cell Migration. Dev Dynam 242, 414-431.

Ghandi M, Huang FW, Jané-Valbuena J, Kryukov GV, Lo CC, McDonald ER 3rd, Barretina J, Gelfand ET, Bielski CM, Li H, Hu K, Andreev-Drakhlin AY, Kim J, Hess JM, Haas BJ, Aguet F, Weir BA, Rothberg MV, Paolella BR, Lawrence MS, Akbani R, Lu Y, Tiv HL, Gokhale PC, de Weck A, Mansour AA, Oh C, Shih J, Hadi K, Rosen Y, Bistline J, Venkatesan K, Reddy A, Sonkin D, Liu M, Lehar J, Korn JM, Porter DA, Jones MD, Golji J, Caponigro G, Taylor JE, Dunning CM, Creech AL, Warren AC, McFarland JM, Zamanighomi M, Kauffmann A, Stransky N, Imielinski M, Maruvka YE, Cherniack AD, Tsherniak A, Vazquez F, Jaffe JD, Lane AA, Weinstock DM, Johannessen CM, Morrissey MP, Stegmeier F, Schlegel R, Hahn WC, Getz G, Mills GB, Boehm JS, Golub TR, Garraway LA, Sellers WR. (2019). Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature 569, 503-508.

Ghiglione, C., Devergne, O., Georgenthum, E., Carballes, F., Medoni, C., Cerezo, D., and Noselli, S. (2002). The Drosophila cytokine receptor Domeless controls border cell migration and epithelial polarization during oogenesis. Development 129, 5437-5447.

Goldfarb, D.S., Corbett, A.H., Mason, D.A., Harreman, M.T., and Adam, S.A. (2004). Importin alpha: a multipurpose nuclear-transport receptor. Trends Cell Biol 14, 505-514.

Gonczy, P., Matunis, E., and DiNardo, S. (1997). bag-of-marbles and benign gonial cell neoplasm act in the germline to restrict proliferation during Drosophila spermatogenesis. Development 124, 4361-4371.

Goode, S., Wei, J., and Kishore, S. (2005). Novel spatiotemporal patterns of epithelial tumor invasion in Drosophila discs large egg chambers. Dev Dyn 232, 855-864.

Gorjanacz, M., Torok, I., Pomozi, I., Garab, G., Szlanka, T., Kiss, I., and Mechler, B.M. (2006). Domains of Importin-alpha2 required for ring canal assembly during Drosophila oogenesis. Journal of structural biology 154, 27-41.

Harrison, D.A., Binari, R., Nahreini, T.S., Gilman, M., and Perrimon, N. (1995). Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. Embo J 14, 2857-2865.

Hauck, B., Gehring, W.J., and Walldorf, U. (1999). Functional analysis of an eye specific enhancer of the eyeless gene in Drosophila. Proc Natl Acad Sci USA 96, 564-569.

Hung, V., Udeshi, N.D., Lam, S.S., Loh, K.H., Cox, K.J., Pedram, K., Carr, S.A., and Ting, A.Y. (2016). Spatially resolved proteomic mapping in living cells with the engineered peroxidase APEX2. Nat Protoc 11, 456-475.

Jang, A.C., Chang, Y.C., Bai, J., and Montell, D. (2009). Border-cell migration requires integration of spatial and temporal signals by the BTB protein Abrupt. Nature cell biology 11, 569-579.

Jiang, L., and Crews, S.T. (2003). The Drosophila dysfusion basic helix-loop-helix (bHLH)-PAS gene controls tracheal fusion and levels of the trachealess bHLH-PAS protein. Molecular and cellular biology 23, 5625-5637.

Jiang, L., and Crews, S.T. (2006). Dysfusion transcriptional control of Drosophila tracheal migration, adhesion, and fusion. Molecular and cellular biology 26, 6547-6556.

Jiang, L., and Crews, S.T. (2007). Transcriptional specificity of Drosophila dysfusion and the control of tracheal fusion cell gene expression. The Journal of biological chemistry 282, 28659-28668.

Johnson, D.E., O'Keefe, R.A., and Grandis, J.R. (2018). Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nature reviews Clinical oncology 15, 234-248.

Lam, S.S., Martell, J.D., Kamer, K.J., Deerinck, T.J., Ellisman, M.H., Mootha, V.K., and Ting, A.Y. (2015). Directed evolution of APEX2 for electron microscopy and proximity labeling. Nature methods 12, 51-54.

Lee, D.D., Hochstetler, A., Murphy, C., Lowe, C.W., and Schwarz, M.A. (2019). A distinct transcriptional profile in response to endothelial monocyte activating polypeptide II is partially mediated by JAK-STAT3 in murine macrophages. Am J Physiol Cell Physiol. 317, C449-C456.

Lee, T.V., Ding, T., Chen, Z., Rajendran, V., Scherr, H., Lackey, M., Bolduc, C., and Bergmann, A. (2008). The E1 ubiquitin-activating enzyme Uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously. Development 135, 43-52.

Lin, H., Yue, L., and Spradling, A.C. (1994). The Drosophila fusome, a germline-specific organelle, contains membrane skeletal proteins and functions in cyst formation. Development 120, 947-956.

Lin, T.H., Yeh, T.H., Wang, T.W., and Yu, J.Y. (2014). The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary. Genetics 198, 1087-1099.

Liu, T.T., Wang, L.H., and Li, Q. (2021). Drosophila Ortholog of Mammalian Immediate-Early Gene Npas4 is Specifically Responsive to Reversal Learning. Neurosci Bull 37, 99-102.

Lott, K., and Cingolani, G. (2011). The importin beta binding domain as a master regulator of nucleocytoplasmic transport. Biochim Biophys Acta 1813, 1578-1592.

Lucas, E.P., Khanal, I., Gaspar, P., Fletcher, G.C., Polesello, C., Tapon, N., and Thompson, B.J. (2013). The Hippo pathway polarizes the actin cytoskeleton during collective migration of Drosophila border cells. J Cell Biol 201, 875-885.

Ma, J., and Cao, X.M. (2006). Regulation of Stat3 nuclear import by importin alpha 5 and importin alpha 7 via two different functional sequence elements. Cell Signal 18, 1117-1126.

Mannix, K.M., Starble, R.M., Kaufman, R.S., and Cooley, L. (2019). Proximity labeling reveals novel interactomes in live Drosophila tissue. Development 146, dev176644.

Manseau, L., Baradaran, A., Brower, D., Budhu, A., Elefant, F., Phan, H., PHilp, A.V., Yang, M.Y., Glover, D., Kaiser, K., et al. (1997). GAL4 enhancer traps expressed in the embryo, larval brain, imaginal discs, and ovary of Drosophila. Dev Dynam 209, 310-322.

Martell, J.D., Deerinck, T.J., Sancak, Y., Poulos, T.L., Mootha, V.K., Sosinsky, G.E., Ellisman, M.H., and Ting, A.Y. (2012). Engineered ascorbate peroxidase as a genetically encoded reporter for electron microscopy. Nat Biotechnol 30, 1143-1148.

Massaly, N., Frances, B., and Mouledous, L. (2015). Roles of the ubiquitin proteasome system in the effects of drugs of abuse. Front Mol Neurosci 7, 99.

Mayor, R., and Etienne-Manneville, S. (2016). The front and rear of collective cell migration. Nat Rev Mol Cell Bio 17, 97-109.

McGuire, S.E., Mao, Z., and Davis, R.L. (2004). Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila. Sci STKE 220, pl6.

McIntosh, B.E., Hogenesch, J.B., and Bradfield, C.A. (2010). Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annual review of physiology 72, 625-645.

McKearin, D., and Ohlstein, B. (1995). A role for the Drosophila bag-of-marbles protein in the differentiation of cystoblasts from germline stem cells. Development 121, 2937-2947.

Melani, M., Simpson, K.J., Brugge, J.S., and Montell, D. (2008). Regulation of cell adhesion and collective cell migration by hindsight and its human homolog RREB1. Curr Biol 18, 532-537.

Montell, D.J. (2003). Border-cell migration: The race is on. Nat Rev Mol Cell Bio 4, 13-24.

Montell, D.J., Rorth, P., and Spradling, A.C. (1992). Slow Border Cells, a Locus Required for a Developmentally Regulated Cell-Migration during Oogenesis, Encodes Drosophila C/Ebp. Cell 71, 51-62.

Montell, D.J., Yoon, W.H., and Starz-Gaiano, M. (2012). Group choreography: mechanisms orchestrating the collective movement of border cells. Nat Rev Mol Cell Bio 13, 631-645.

Moser, M., Knoth, R., Bode, C., and Patterson, C. (2004). LE-PAS, a novel Arnt-dependent HLH-PAS protein, is expressed in limbic tissues and transactivates the CNS midline enhancer element. Mol Brain Res 128, 141-149.

Murphy, A.M., and Montell, D.J. (1996). Cell type-specific roles for Cdc42, Rac, and RhoL in Drosophila oogenesis. J Cell Biol 133, 617-630.

Nusinow DP, Szpyt J, Ghandi M, Rose CM, McDonald ER 3rd, Kalocsay M, Jané-Valbuena J, Gelfand E, Schweppe DK, Jedrychowski M, Golji J, Porter DA, Rejtar T, Wang YK, Kryukov GV, Stegmeier F, Erickson BK, Garraway LA, Sellers WR, Gygi SP. (2020). Quantitative Proteomics of the Cancer Cell Line Encyclopedia. Cell 180, 387-402 e316.

O'Shea, J.J., Gadina, M., and Schreiber, R.D. (2002). Cytokine signaling in 2002: New surprises in the Jak/Stat pathway. Cell 109, S121-S131.

Ooe, N., Saito, K., Mikami, N., Nakatuka, I., and Kaneko, H. (2004). Identification of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 competitive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression. Molecular and cellular biology 24, 608-616.

Park, J.S., Choi, S.Y., Lee, J.H., Lee, M., Nam, E.S., Jeong, A.L., Lee, S., Han, S., Lee, M.S., Lim, J.S., et al. (2013). Interleukin-32 beta stimulates migration of MDA-MB-231 and MCF-7cells via the VEGF-STAT3 signaling pathway. Cell Oncol 36, 493-503.

Parks, S., Wakimoto, B., and Spradling, A. (1986). Replication and Expression of an X-Linked Cluster of Drosophila Chorion Genes. Dev Biol 117, 294-305.

Pinheiro, E.M., and Montell, D.J. (2004). Requirement for Par-6 and Bazooka in Drosophila border cell migration. Development 131, 5243-5251.

Ploski, J.E., Monsey, M.S., Nguyen, T., DiLeone, R.J., and Schafe, G.E. (2011). The neuronal PAS domain protein 4 (Npas4) is required for new and reactivated fear memories. PloS one 6, e23760.

Prasad, M., Wang, X., He, L., and Montell, D.J. (2011). Border cell migration: a model system for live imaging and genetic analysis of collective cell movement. Methods Mol Biol 769, 277-286.

Raices, M., and D'Angelo, M.A. (2012). Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions. Nat Rev Mol Cell Bio 13, 687-699.

Rakesh, K., and Agrawal, D.K. (2005). Controlling cytokine signaling by constitutive inhibitors. Biochem Pharmacol 70, 649-657.

Ramamoorthi, K., Fropf, R., Belfort, G.M., Fitzmaurice, H.L., McKinney, R.M., Neve, R.L., Otto, T., and Lin, Y. (2011). Npas4 regulates a transcriptional program in CA3 required for contextual memory formation. Science 334, 1669-1675.

Rorth, P. (2009). Collective Cell Migration. Annu Rev Cell Dev Bi 25, 407-429.

Rorth, P. (2012). Fellow travellers: emergent properties of collective cell migration. Embo Rep 13, 984-991.

Rorth, P., Szabo, K., Bailey, A., Laverty, T., Rehm, J., Rubin, G.M., Weigmann, K., Milan, M., Benes, V., Ansorge, W., et al. (1998). Systematic gain-of-function genetics in Drosophila. Development 125, 1049-1057.

Rytinki, M.M., Kaikkonen, S., Pehkonen, P., Jaaskelainen, T., and Palvimo, J.J. (2009). PIAS proteins: pleiotropic interactors associated with SUMO. Cell Mol Life Sci 66, 3029-3041.

Saadin, A., and Starz-Galano, M. (2016). Circuitous Genetic Regulation Governs a Straightforward Cell Migration. Trends Genet 32, 660-673.

Sano, S., Itami, S., Takeda, K., Tarutani, M., Yamaguchi, Y., Miura, H., Yoshikawa, K., Akira, S., and Takeda, J. (1999). Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. Embo J 18, 4657-4668.

Scarpa, E., and Mayor, R. (2016). Collective cell migration in development. J Cell Biol 212, 143-155.

Shen, R., Weng, C., Yu, J., and Xie, T. (2009). eIF4A controls germline stem cell self-renewal by directly inhibiting BAM function in the Drosophila ovary. Proc Natl Acad Sci U S A 106, 11623-11628.

Silver, D.L., and Montell, D.J. (2001). Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila. Cell 107, 831-841.

Sotillos, S., Krahn, M., Espinosa-Vazquez, J.M., and Hombria, J.C. (2013). Src kinases mediate the interaction of the apical determinant Bazooka/PAR3 with STAT92E and increase signalling efficiency in Drosophila ectodermal cells. Development 140, 1507-1516.

Starr, R., and Hilton, D.J. (1999). Negative regulation of the JAK/STAT pathway. Bioessays 21, 47-52.

Starz-Gaiano, M., Melani, M., Wang, X.B., Meinhardt, H., and Montell, D.J. (2008). Feedback inhibition of JAK/STAT signaling by apontic is required to limit an invasive cell population. Developmental cell 15, 330-330.

Stempfle, D., Kanwar, R., Loewer, A., Fortini, M.E., and Merdes, G. (2010). In Vivo Reconstitution of gamma-Secretase in Drosophila Results in Substrate Specificity. Molecular and cellular biology 30, 3165-3175.

Strambio-De-Castillia, C., Niepel, M., and Rout, M.P. (2010). The nuclear pore complex: bridging nuclear transport and gene regulation. Nat Rev Mol Cell Bio 11, 490-501.

Sun, X., and Lin, Y. (2016). Npas4: Linking Neuronal Activity to Memory. Trends in neurosciences 39, 264-275.

Sutherland, D., Samakovlis, C., and Krasnow, M.A. (1996). Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell 87, 1091-1101.

Suzanne, M. (2016). Molecular and cellular mechanisms involved in leg joint morphogenesis. Semin Cell Dev Biol 55, 131-138.

Takeda, K., Noguchi, K., Shi, W., Tanaka, T., Matsumoto, M., Yoshida, N., Kishimoto, T., and Akira, S. (1997). Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci USA 94, 3801-3804.

Teng, Y., Ross, J.L., and Cowell, J.K. (2014). The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. Jak-Stat 3, e28086.

Torres, I.L., Lopez-Schier, H., and St Johnston, D. (2003). A Notch/Delta-dependent relay mechanism establishes anterior-posterior polarity in Drosophila. Developmental cell 5, 547-558.

Trivedi, S., and Starz-Gaiano, M. (2018). Drosophila Jak/STAT Signaling: Regulation and Relevance in Human Cancer and Metastasis. Int J Mol Sci 19, 4056.

Tsai, Y.C., and Sun, Y.H. (2004). Long-range effect of Upd, a ligand pathway, on cell cycle in Drosophila for Jak/STAT eye development. Genesis 39, 141-153.

Venken, K.J., Carlson, J.W., Schulze, K.L., Pan, H., He, Y., Spokony, R., Wan, K.H., Koriabine, M., de Jong, P.J., White, K.P., et al. (2009). Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster. Nature methods 6, 431-434.

Verhoeven, Y., Tilborghs, S., Jacobs, J., De Waele, J., Quatannens, D., Deben, C., Prenen, H., Pauwels, P., Trinh, X.B., Wouters, A., et al. (2020). The potential and controversy of targeting STAT family members in cancer. Seminars in cancer biology 60, 41-56.

Weijer, C.J. (2009). Collective cell migration in development. Journal of cell science 122, 3215-3223.

Wu, D., and Rastinejad, F. (2017). Structural characterization of mammalian bHLH-PAS transcription factors. Current opinion in structural biology 43, 1-9.

Xi, R., McGregor, J.R., and Harrison, D.A. (2003). A gradient of JAK pathway activity patterns the anterior-posterior axis of the follicular epithelium. Developmental cell 4, 167-177.

Xu, X.H., Yang, C.D., Chen, J., Liu, J.Y., Li, P.A., Shi, Y., and Yu, P.W. (2018). Interleukin-23 promotes the migration and invasion of gastric cancer cells by inducing epithelial-to-mesenchymal transition via the STAT3 pathway. Biochem Bioph Res Co 499, 273-278.

Yan, R.Q., Small, S., Desplan, C., Dearolf, C.R., and Darnell, J.E. (1996). Identification of a Stat gene that functions in Drosophila development. Cell 84, 421-430.

Yoon, W.H., Meinhardt, H., and Montell, D.J. (2011). miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold. Nature cell biology 13, 1062-1069.

Yu, H., Lee, H., Herrmann, A., Buettner, R., and Jove, R. (2014). Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14, 736-746.

Zeidler, M.P., and Bausek, N. (2013). The Drosophila JAK-STAT pathway. Jak-Stat 2, e25353.

Zeidler, M.P., Perrimon, N., and Strutt, D.I. (1999). Polarity determination in the Drosophila eye: a novel role for unpaired and JAK/STAT signaling. Genes Dev 13, 1342-1353.