Catching the wave

doi:10.1126/science.abg8077

GSTDTAP > 气候变化

DOI	10.1126/science.abg8077
	Catching the wave
	Sophie Hambleton
	2021-03-26
发表期刊	Science
出版年	2021
英文摘要	A central paradox in many inborn errors of immunity is the conjunction of autoimmune and autoinflammatory pathology with susceptibility to infection. On page 1333 of this issue, Liu et al. ([ 1 ][1]) explore the molecular mechanisms of immune dysfunction in mice whose T cells lack expression of the cytoskeletal regulatory protein WAVE2 (Wiskott-Aldrich syndrome protein family member 2). Without WAVE2, T cells do not move around normally, interact closely with antigen-presenting cells, nor generate protective immune responses ([ 1 ][1]–[ 3 ][2]). Nonetheless, they are adept at infiltrating nonlymphoid tissues and exhibit dysregulated proliferation and pro-inflammatory effector function, associated with excessive activity of mechanistic target of rapamycin (mTOR). Treatment of WAVE2-deficient mice with an mTOR inhibitor restored T cell quiescence and immune homeostasis. The description of WAVE2 as a negative regulator of mTOR, the master regulator of lymphocyte metabolism, draws attention to an underexplored, and eminently druggable, candidate mechanism for inflammatory complications of immunocytoskeletal disorders. To do their job effectively, T cells need to move to the correct location, sense antigen by forming an immunological synapse (IS), and respond appropriately. This requires dynamic reorganization of the actin cytoskeleton at the IS to support the receipt of an array of cell-associated and soluble signals, as well as the polarized delivery of effector responses such as cytotoxicity molecules and cytokines ([ 4 ][3]) (see the figure). Downstream of T cell receptor (TCR) signaling, WAVE2 is activated by the cell membrane–associated small guanosine triphosphatase RAC1 and nucleates actin branching by actin-related protein 2 (ARP2)–ARP3 ([ 2 ][4]). Assembly of the branched actin network at the periphery of the IS drives both local spreading (lamellipodia formation) and retrograde flow toward the center of the IS ([ 4 ][3]). Mutations within the cytoskeletal machinery are associated with impaired T cell activation and function in a range of primary immunodeficiency disorders, often producing inflammatory complications as well as susceptibility to infections and lymphoma ([ 5 ][5]). However, WAVE2 deficiency has not been described in humans and its deletion in mice causes embryonic lethality. Recently, several groups described a human disorder caused by deficiency of a related cytoskeletal regulator, hematopoietic protein 1 (HEM1) ([ 6 ][6]–[ 8 ][7]). Affected children manifest a mixture of infection and prominent immune dysregulation in the form of autoimmunity, lymphoproliferation, and in one-third of patients, the potentially fatal inflammatory syndrome hemophagocytic lymphohistiocytosis. Because HEM1 and WAVE2 are mutually stabilizing within a multiprotein WAVE-regulatory complex (WRC), deficiency of either protein leads to reduced expression of both ([ 1 ][1], [ 2 ][4], [ 6 ][6], [ 7 ][8]). Together, HEM1-deficient humans and mice with WAVE2-deficient T cells offer a powerful opportunity to characterize immune dysregulation in the absence of the WRC. Like WAVE2-deficient mouse T cells, human HEM1-deficient T and B lymphocytes exhibit impaired formation of IS and lamellipodia ([ 6 ][6], [ 7 ][8]). WRC-deficient T cells of both species also showed hyperproliferation, cytokine hypersecretion, and excessive degranulation upon stimulation ([ 1 ][1], [ 6 ][6]). Liu et al. discovered that naïve WAVE2-deficient T cells showed markedly excessive activation of mTOR both at baseline and upon stimulation. mTOR is a dynamically regulated master coordinator of the metabolic reprogramming that supports T cell activation, exit from quiescence, and differentiation ([ 9 ][9]–[ 11 ][10]). Pathological activation of mTOR in the human immune system, caused by gain-of-function mutations in the upstream regulator phosphoinositide-3-kinase-δ, leads to immunodeficiency with prominent lymphoproliferative features and has been called a TOR-opathy ([ 12 ][11], [ 13 ][12]). Conversely, pharmacologic inhibitors of mTOR restrain T cell proliferation and skew cell fate away from effector function in favor of a quiescent or even regulatory state ([ 11 ][10]). Naïve WAVE2-deficient T cells showed clear evidence of overactivity of both pathways through which mTOR signals: mTOR complex 1 (mTORC1) and mTORC2 ([ 1 ][1]). Administration of an mTOR inhibitor reversed these biochemical abnormalities, normalized cellular responses to TCR stimulation, and rescued mice from lethal autoimmunity and lymphoproliferation. Liu et al. provide strong evidence that WAVE2 interacts directly with mTOR, which appears to sequester mTOR away from regulatory-associated protein of mTOR (RAPTOR; mTORC1) and rapamycin-insensitive companion of mTOR (RICTOR; mTORC2). This raises the possibility that WAVE2 functions as an endogenous competitive inhibitor of both pathways. Indeed, loss of WAVE2 led to inappropriate mTOR activity and its overexpression inhibited mTOR. This suggests that WAVE2 influences mTOR “tone” within a physiologically relevant dynamic range, which is in keeping with a role in the metabolic restraint required for peripheral T cell quiescence and immune homeostasis. How WAVE2-mTOR interaction might be modulated by cellular activation status—in particular, the impact of posttranslational modification and relocalization within the cell—remains to be determined. One model would be that T cell activation releases mTOR from tonic inhibition at least in part by drawing WAVE2 away to participate in actin-remodeling events at the IS. ![Figure][13] The T cell immunological synapseGRAPHIC: N. CARY/ SCIENCE That activity of mTOR and the cytoskeleton should be linked is perhaps not unexpected. A cooperative relationship between mTORC2 expression and actin remodeling was postulated at the time RICTOR was discovered because reducing RICTOR expression prevented lamellipodia formation and cortical actin polymerization in epithelial cells ([ 14 ][14], [ 15 ][15]). It would be interesting to investigate whether mTOR-WAVE2 interaction is inappropriately increased in this context, especially in T cells. More recently, human WAVE2 and HEM1 were reported to bind to RICTOR (although not mTOR itself) ([ 6 ][6]). This interaction was proposed to activate mTOR because human HEM1-deficient T lymphoblasts were impaired for overall TCR responsiveness and AKT-Ser473 phosphorylation (downstream of mTORC2) ([ 6 ][6]). Reduced AKT activity was also reported in B cells from patients with HEM1 deficiency ([ 7 ][8]). This lack of congruence between findings in WAVE2-deficient mice and HEM1-deficient humans is unexpected and merits further attention. Although true interspecies differences cannot be excluded, the similarity in phenotype instead suggests a common molecular mechanism. mTOR activity is inherently sensitive to confounding variables such as lymphocyte proliferative history, immunosenescence, and immunosuppressive therapy. It will be interesting, and could have therapeutic importance, to clarify the nature of the mutual interaction between mTOR and the WRC, its modulation by upstream signals, and potential contribution to pathology in a range of human immune disorders. 1. [↵][16]1. M. Liu et al ., Science 371, eaaz4544 (2021). [OpenUrl][17][Abstract/FREE Full Text][18] 2. [↵][19]1. J. C. Nolz et al ., Curr. Biol. 16, 24 (2006). [OpenUrl][20][CrossRef][21][PubMed][22][Web of Science][23] 3. [↵][24]1. D. D. Billadeau, 2. J. C. Nolz, 3. T. S. Gomez , Nat. Rev. Immunol. 7, 131 (2007). [OpenUrl][25][CrossRef][26][PubMed][27][Web of Science][28] 4. [↵][29]1. J. A. Hammer, 2. J. C. Wang, 3. M. Saeed, 4. A. T. Pedrosa , Annu. Rev. Immunol. 37, 201 (2019). [OpenUrl][30][CrossRef][31] 5. [↵][32]1. R. Papa, 2. F. Penco, 3. S. Volpi, 4. M. Gattorno , Front. Immunol. 11, 604206 (2021). [OpenUrl][33] 6. [↵][34]1. S. A. Cook et al ., Science 369, 202 (2020). [OpenUrl][35][Abstract/FREE Full Text][36] 7. [↵][37]1. E. Salzer et al ., Sci. Immunol. 5, eabc3979 (2020). [OpenUrl][38][Abstract/FREE Full Text][39] 8. [↵][40]1. C. N. Castro et al ., J. Exp. Med. 217, e20192275 (2020). [OpenUrl][41][CrossRef][42][PubMed][43] 9. [↵][44]1. K. Yang et al ., Immunity 39, 1043 (2013). [OpenUrl][45][CrossRef][46][PubMed][47][Web of Science][48] 10. 1. R. A. Saxton, 2. D. M. Sabatini , Cell 168, 960 (2017). [OpenUrl][49][CrossRef][50][PubMed][51] 11. [↵][52]1. C. H. Patel, 2. J. D. Powell , Curr. Opin. Immunol. 46, 82 (2017). [OpenUrl][53][CrossRef][54] 12. [↵][55]1. C. L. Lucas, 2. A. Chandra, 3. S. Nejentsev, 4. A. M. Condliffe, 5. K. Okkenhaug , Nat. Rev. Immunol. 16, 702 (2016). [OpenUrl][56][CrossRef][57] 13. [↵][58]1. S. Jung, 2. L. Gámez-Díaz, 3. M. Proietti, 4. B. Grimbacher , Front. Immunol. 9, 966 (2018). [OpenUrl][59][CrossRef][60][PubMed][61] 14. [↵][62]1. D. D. Sarbassov et al ., Curr. Biol. 14, 1296 (2004). [OpenUrl][63][CrossRef][64][PubMed][65][Web of Science][66] 15. [↵][67]1. E. Jacinto et al ., Nat. Cell Biol. 6, 1122 (2004). [OpenUrl][68][CrossRef][69][PubMed][70][Web of Science][71] Acknowledgments: S.H. is supported by the Wellcome Trust. [1]: #ref-1 [2]: #ref-3 [3]: #ref-4 [4]: #ref-2 [5]: #ref-5 [6]: #ref-6 [7]: #ref-8 [8]: #ref-7 [9]: #ref-9 [10]: #ref-11 [11]: #ref-12 [12]: #ref-13 [13]: pending:yes [14]: #ref-14 [15]: #ref-15 [16]: #xref-ref-1-1 "View reference 1 in text" [17]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DLiu%26rft.auinit1%253DM.%26rft.volume%253D371%26rft.issue%253D6536%26rft.spage%253Deaaz4544%26rft.epage%253Deaaz4544%26rft.atitle%253DWAVE2%2Bsuppresses%2BmTOR%2Bactivation%2Bto%2Bmaintain%2BT%2Bcell%2Bhomeostasis%2Band%2Bprevent%2Bautoimmunity%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaz4544%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [18]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjE3OiIzNzEvNjUzNi9lYWF6NDU0NCI7czo0OiJhdG9tIjtzOjIzOiIvc2NpLzM3MS82NTM2LzEzMDkuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [19]: #xref-ref-2-1 "View reference 2 in text" [20]: {openurl}?query=rft.jtitle%253DCurrent%2Bbiology%2B%253A%2B%2BCB%26rft.stitle%253DCurr%2BBiol%26rft.aulast%253DNolz%26rft.auinit1%253DJ.%2BC.%26rft.volume%253D16%26rft.issue%253D1%26rft.spage%253D24%26rft.epage%253D34%26rft.atitle%253DThe%2BWAVE2%2Bcomplex%2Bregulates%2Bactin%2Bcytoskeletal%2Breorganization%2Band%2BCRAC-mediated%2Bcalcium%2Bentry%2Bduring%2BT%2Bcell%2Bactivation.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cub.2005.11.036%26rft_id%253Dinfo%253Apmid%252F16401421%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [21]: /lookup/external-ref?access_num=10.1016/j.cub.2005.11.036&link_type=DOI [22]: /lookup/external-ref?access_num=16401421&link_type=MED&atom=%2Fsci%2F371%2F6536%2F1309.atom [23]: /lookup/external-ref?access_num=000234704900019&link_type=ISI [24]: #xref-ref-3-1 "View reference 3 in text" [25]: {openurl}?query=rft.jtitle%253DNature%2Breviews.%2BImmunology%26rft.stitle%253DNat%2BRev%2BImmunol%26rft.aulast%253DBilladeau%26rft.auinit1%253DD.%2BD.%26rft.volume%253D7%26rft.issue%253D2%26rft.spage%253D131%26rft.epage%253D143%26rft.atitle%253DRegulation%2Bof%2BT-cell%2Bactivation%2Bby%2Bthe%2Bcytoskeleton.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnri2021%26rft_id%253Dinfo%253Apmid%252F17259969%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [26]: /lookup/external-ref?access_num=10.1038/nri2021&link_type=DOI [27]: /lookup/external-ref?access_num=17259969&link_type=MED&atom=%2Fsci%2F371%2F6536%2F1309.atom [28]: /lookup/external-ref?access_num=000243839200012&link_type=ISI [29]: #xref-ref-4-1 "View reference 4 in text" [30]: {openurl}?query=rft.jtitle%253DAnnu.%2BRev.%2BImmunol.%26rft.volume%253D37%26rft.spage%253D201%26rft_id%253Dinfo%253Adoi%252F10.1146%252Fannurev-immunol-042718-041341%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [31]: /lookup/external-ref?access_num=10.1146/annurev-immunol-042718-041341&link_type=DOI [32]: #xref-ref-5-1 "View reference 5 in text" [33]: {openurl}?query=rft.jtitle%253DFront.%2BImmunol.%26rft.volume%253D11%26rft.spage%253D604206%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [34]: #xref-ref-6-1 "View reference 6 in text" [35]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DCook%26rft.auinit1%253DS.%2BA.%26rft.volume%253D369%26rft.issue%253D6500%26rft.spage%253D202%26rft.epage%253D207%26rft.atitle%253DHEM1%2Bdeficiency%2Bdisrupts%2BmTORC2%2Band%2BF-actin%2Bcontrol%2Bin%2Binherited%2Bimmunodysregulatory%2Bdisease%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aay5663%26rft_id%253Dinfo%253Apmid%252F32647003%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [36]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNjkvNjUwMC8yMDIiO3M6NDoiYXRvbSI7czoyMzoiL3NjaS8zNzEvNjUzNi8xMzA5LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [37]: #xref-ref-7-1 "View reference 7 in text" [38]: {openurl}?query=rft.jtitle%253DScience%2BImmunology%26rft.stitle%253DSci.%2BImmunol.%26rft.aulast%253DSalzer%26rft.auinit1%253DE.%26rft.volume%253D5%26rft.issue%253D49%26rft.spage%253Deabc3979%26rft.epage%253Deabc3979%26rft.atitle%253DThe%2Bcytoskeletal%2Bregulator%2BHEM1%2Bgoverns%2BB%2Bcell%2Bdevelopment%2Band%2Bprevents%2Bautoimmunity%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fsciimmunol.abc3979%26rft_id%253Dinfo%253Apmid%252F32646852%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [39]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6ImltbXVub2xvZ3kiO3M6NToicmVzaWQiO3M6MTM6IjUvNDkvZWFiYzM5NzkiO3M6NDoiYXRvbSI7czoyMzoiL3NjaS8zNzEvNjUzNi8xMzA5LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [40]: #xref-ref-8-1 "View reference 8 in text" [41]: {openurl}?query=rft.jtitle%253DJ.%2BExp.%2BMed.%26rft.volume%253D217%26rft.spage%253De20192275%26rft_id%253Dinfo%253Adoi%252F10.1084%252Fjem.20192275%26rft_id%253Dinfo%253Apmid%252F32766723%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [42]: /lookup/external-ref?access_num=10.1084/jem.20192275&link_type=DOI [43]: /lookup/external-ref?access_num=32766723&link_type=MED&atom=%2Fsci%2F371%2F6536%2F1309.atom [44]: #xref-ref-9-1 "View reference 9 in text" [45]: {openurl}?query=rft.jtitle%253DImmunity%26rft.volume%253D39%26rft.spage%253D1043%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.immuni.2013.09.015%26rft_id%253Dinfo%253Apmid%252F24315998%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [46]: /lookup/external-ref?access_num=10.1016/j.immuni.2013.09.015&link_type=DOI [47]: /lookup/external-ref?access_num=24315998&link_type=MED&atom=%2Fsci%2F371%2F6536%2F1309.atom [48]: /lookup/external-ref?access_num=000330951000011&link_type=ISI [49]: {openurl}?query=rft.jtitle%253DCell%26rft.volume%253D168%26rft.spage%253D960%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cell.2017.02.004%26rft_id%253Dinfo%253Apmid%252F28283069%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [50]: /lookup/external-ref?access_num=10.1016/j.cell.2017.02.004&link_type=DOI [51]: /lookup/external-ref?access_num=28283069&link_type=MED&atom=%2Fsci%2F371%2F6536%2F1309.atom [52]: #xref-ref-11-1 "View reference 11 in text" [53]: {openurl}?query=rft.jtitle%253DCurr.%2BOpin.%2BImmunol.%26rft.volume%253D46%26rft.spage%253D82%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.coi.2017.04.006%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [54]: /lookup/external-ref?access_num=10.1016/j.coi.2017.04.006&link_type=DOI [55]: #xref-ref-12-1 "View reference 12 in text" [56]: {openurl}?query=rft.jtitle%253DNat.%2BRev.%2BImmunol.%26rft.volume%253D16%26rft.spage%253D702%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnri.2016.93%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [57]: /lookup/external-ref?access_num=10.1038/nri.2016.93&link_type=DOI [58]: #xref-ref-13-1 "View reference 13 in text" [59]: {openurl}?query=rft.jtitle%253DFront.%2BImmunol.%26rft.volume%253D9%26rft.spage%253D966%26rft_id%253Dinfo%253Adoi%252F10.3389%252Ffimmu.2018.00966%26rft_id%253Dinfo%253Apmid%252F29867948%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [60]: /lookup/external-ref?access_num=10.3389/fimmu.2018.00966&link_type=DOI [61]: /lookup/external-ref?access_num=29867948&link_type=MED&atom=%2Fsci%2F371%2F6536%2F1309.atom [62]: #xref-ref-14-1 "View reference 14 in text" [63]: {openurl}?query=rft.jtitle%253DCurrent%2Bbiology%2B%253A%2B%2BCB%26rft.stitle%253DCurr%2BBiol%26rft.aulast%253DSarbassov%26rft.auinit1%253DD.%2BD.%26rft.volume%253D14%26rft.issue%253D14%26rft.spage%253D1296%26rft.epage%253D1302%26rft.atitle%253DRictor%252C%2Ba%2Bnovel%2Bbinding%2Bpartner%2Bof%2BmTOR%252C%2Bdefines%2Ba%2Brapamycin-insensitive%2Band%2Braptor-independent%2Bpathway%2Bthat%2Bregulates%2Bthe%2Bcytoskeleton.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cub.2004.06.054%26rft_id%253Dinfo%253Apmid%252F15268862%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [64]: /lookup/external-ref?access_num=10.1016/j.cub.2004.06.054&link_type=DOI [65]: /lookup/external-ref?access_num=15268862&link_type=MED&atom=%2Fsci%2F371%2F6536%2F1309.atom [66]: /lookup/external-ref?access_num=000223038600029&link_type=ISI [67]: #xref-ref-15-1 "View reference 15 in text" [68]: {openurl}?query=rft.jtitle%253DNature%2BCell%2BBiology%26rft.stitle%253DNature%2BCell%2BBiology%26rft.aulast%253DJacinto%26rft.auinit1%253DE.%26rft.volume%253D6%26rft.issue%253D11%26rft.spage%253D1122%26rft.epage%253D1128%26rft.atitle%253DMammalian%2BTOR%2Bcomplex%2B2%2Bcontrols%2Bthe%2Bactin%2Bcytoskeleton%2Band%2Bis%2Brapamycin%2Binsensitive.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fncb1183%26rft_id%253Dinfo%253Apmid%252F15467718%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [69]: /lookup/external-ref?access_num=10.1038/ncb1183&link_type=DOI [70]: /lookup/external-ref?access_num=15467718&link_type=MED&atom=%2Fsci%2F371%2F6536%2F1309.atom [71]: /lookup/external-ref?access_num=000224816700018&link_type=ISI
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/321083
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Sophie Hambleton. Catching the wave[J]. Science,2021.
APA	Sophie Hambleton.(2021).Catching the wave.Science.
MLA	Sophie Hambleton."Catching the wave".Science (2021).