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Cosima T. Baldari
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Patrussi, L.; Capitani, N.; Baldari, C.T. The Adaptor Protein p66Shc. Encyclopedia. Available online: https://encyclopedia.pub/entry/2981 (accessed on 16 November 2024).
Patrussi L, Capitani N, Baldari CT. The Adaptor Protein p66Shc. Encyclopedia. Available at: https://encyclopedia.pub/entry/2981. Accessed November 16, 2024.
Patrussi, Laura, Nagaja Capitani, Cosima T. Baldari. "The Adaptor Protein p66Shc" Encyclopedia, https://encyclopedia.pub/entry/2981 (accessed November 16, 2024).
Patrussi, L., Capitani, N., & Baldari, C.T. (2020, November 11). The Adaptor Protein p66Shc. In Encyclopedia. https://encyclopedia.pub/entry/2981
Patrussi, Laura, et al. "The Adaptor Protein p66Shc." Encyclopedia. Web. 11 November, 2020.
The Adaptor Protein p66Shc
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This entry is adapted from the peer-reviewed paper 10.3390/cancers12041006

p66Shc is an adaptor protein with anti-mitogenic, anti-chemotactic, pro-apoptotic and pro-oxidant activities.  Neoplastic B cells from chronic lymphocytic leukemia (CLL) patients  have a profound deficiency in the expression of p66Shc which results in leukemic cell resistance to apoptosis and in an altered balance between homing and egress receptors that control B cell homing to and residency into the pro-survival lymphoid niche. Ablation of the gene encoding p66Shc in the Eμ-TCL1 mouse model of human CLL worsens disease presentation  by promoting leukemic cell invasiveness, providing in vivo evidence of the pathogenic role of the p66Shc defect in CLL pathogenesis. Here we briefly summarize the functions of p66Shc in lymphocytes, focalizing on the mechanisms exploited by p66Shc to control B cell trafficking and the abnormalities in this process caused by p66Shc deficiency in CLL. 

p66Shc CLL receptor recycling BCL2 apoptosis homing receptors lymphocyte trafficking

1. Introduction

The p66Shc adaptor is a negative regulator of survival signaling and a promoter of oxidative stress-dependent apoptosis [1]. These activities rely on its CH2-PTB-CH1-SH2 modular structure, with three phosphorylatable tyrosines, a phosphorylatable serine and a cytochrome-c binding domain [1] that make this molecule an important hub at the cross-roads of cell signaling and cellular response to stress.

2. Functions of p66Shc

2.1 p66Shc negatively regulates antigen receptor signaling and chemotaxis in lymphocytes

Once recruited to the activated antigen receptors, p66Shc antagonizes TCR-, BCR- and FcεRI-triggered mitogenic signaling by recruiting/sequestering key signaling molecules, thereby inhibiting downstream pathways [1][2][3][4]. In p66Shc-/- mice, lymphocytes and mast cells display enhanced immune responses in vitro and in vivo [3][4][5]. p66Shc also acts as a negative regulator of the chemotactic responses triggered by the chemokine receptors CXCR4 and CXCR5 in B cells [6][7] highlighting its potential to tune down both chemotactic and immune responses.

2.2 p66Shc promotes lymphocyte apoptosis and autophagy/mitophagy

p66Shc is a mediator of apoptotic responses to oxidative stress [8]. In lymphocytes, its expression results in increased susceptibility to apoptosis induced by pharmacological and physiological stimuli [2][9][10]. p66Shc exerts its pro-apoptotic activity by impairing mitochondrial integrity [9] and modulating the balance of pro- and anti-apoptotic members of the BCL2 family towards the pro-apoptotic ones [11]. Disruption of the respiratory chain by p66Shc results moreover in autophagy/mitophagy by promoting local phagophore assembly [12][13], placing p66Shc at the cross-roads of multiple pathways that control cell survival.

3. The pathogenic effects of altered p66Shc expression in CLL

Abnormalities in p66Shc expression are associated to the development of several diseases, including liver fibrosis [14], Alzheimer's disease [15] and immune disorders. Mice lacking p66Shc expression develop systemic lupus-like autoimmunity [5], underscoring the importance of its regulation in disease control.

p66Shc expression is profoundly impaired in leukemic cells from patients with chronic lymhocytic leukemia (CLL) [2], a B-cell neoplasia characterized by a heterogeneous clinical course [16]. Importantly, the lowest residual p66Shc levels were found in leukemic cells from patients with aggressive disease [2]. This observation was recapitulated in the Eμ-TCL1 mouse model of human CLL [10][17]. p66Shc ablation in Eμ-TCL1 mice resulted in enhanced disease aggressiveness, associated with prolonged survival and chemoresistance of the p66Shc-deficient leukemic cells [10].

3.1. p66Shc deficiency alters the BCL2 family balance

An altered ratio of pro- versus anti-apoptotic members of the BCL2 family of apoptosis-regulating proteins contributes to the shift of leukemic CLL cells towards survival and correlates with poor prognosis [18]. p66Shc deficiency in both CLL and Eμ-TCL1 leukemic cells contributes to this altered balance [2][10], which is normalized by forced p66Shc expression [2], providing proof-of-concept that p66Shc is implicated in the transcriptional regulation of BCL2 proteins.

3.2. p66Shc deficiency affects expression and recycling of trafficking receptors

CLL cells are characterized by trafficking abnormalities that promote leukemic cell residency in the pro-survival lymphoid stromal niche [19][20]. These alterations are associated with abnormally high surface levels of the chemokine receptors CXCR4, CCR7, CXCR5, CXCR3 and CCR2 [10][20], whose enhanced expression inversely correlates with residual p66Shc [10][21]. Conversely, p66Shc deficiency in CLL cells directly correlates to their abnormally low levels of the sphingosine-1-phosphate receptor S1PR1 [21] which controls lymphocyte egress from lymphoid organs [22],  contributing to the local accumulation of CLL cells [20]. Forced p66Shc expression in CLL cells normalizes the expression of these receptors and restores chemotaxis, while the expression of a redox-deficient p66Shc mutant does not [10][21], suggesting that neoplastic cell residency in microenvironmental niches [10] depends on the ROS-elevating activity of p66Shc.

In addition to transcriptional regulation, CLL cells also take advantage of recycling to rapidly enhance the surface levels of the homing receptors CCR7 and CXCR4 through their redistribution from the intracellular pool to the plasma membrane [23]. This enhancement is caused in part by the enhanced dephosphorylating activity of the Ca2+-dependent phosphoserine phosphatase PP2B [24], which promotes transit of recycling CXCR4 and CCR7 from the endosomal compartment to the cell surface [7]. This enhancement is reversed by forced p66Shc expression, which attenuates receptor-dependent Ca2+ mobilization [6][7]. Together, these mechanisms contribute to amplify the surface levels of these receptors, promoting leukemic cell homing to the lymphoid niche.

4. Conclusions and future perspectives

Current evidence highlights the multifaceted role of p66Shc in B cells and the profound consequences of its deficiency on B-cell apoptosis, survival and chemotaxis, and on the B-cell interplay with the stromal microenvironment, all of which are dysregulated in CLL cells [10]. The abnormalities harboured by CLL cells are reversed by forced p66Shc expression in vitro [7][21], making p66Shc reconstitution an attractive therapeutic target.

p66shc is regulated by the transcription factor STAT4, a crucial mediator of the IL-12-triggered signaling pathway [25]. STAT4 expression is profoundly impaired in CLL cells [26]. Interestingly IL-12, by triggering STAT4 activation, coordinately increases STAT4 and p66Shc expression and enhances B-cell apoptosis [26]. This suggests the possibility that STAT4 agonists able to stimulate the residual STAT4 in CLL cells could normalize p66Shc expression. However, a compound that selectively targets this pathway remains to be identified.

References

  1. Francesca Finetti; Maria Teresa Savino; Cosima T. Baldari; Positive and negative regulation of antigen receptor signaling by the Shc family of protein adapters. Immunological Reviews 2009, 232, 115-134, 10.1111/j.1600-065x.2009.00826.x.
  2. Nagaja Capitani; Orso Maria Lucherini; Elisa Sozzi; Micol Ferro; N. Giommoni; Francesca Finetti; Giulia De Falco; Emanuele Cencini; Donatella Raspadori; Pier Giuseppe Pelicci; et al.Francesco LauriaFrancesco ForconiCosima T. Baldari Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia. Blood 2010, 115, 3726-3736, 10.1182/blood-2009-08-239244.
  3. Cristina Ulivieri; Daniela Fanigliulo; Giulia Masi; Maria Teresa Savino; Alessandra Gamberucci; Pier Giuseppe Pelicci; Cosima T. Baldari; p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells. The Journal of Immunology 2011, 186, 5095-5106, 10.4049/jimmunol.1001391.
  4. Giulia Masi; David Mercati; Elisa Vannuccini; Eugenio Paccagnini; Maria Giovanna Riparbelli; Pietro Lupetti; Pier Giuseppe Pelicci; Cosima T. Baldari; Cristina Ulivieri; p66Shc regulates vesicle-mediated secretion in mast cells by affecting F-actin dynamics. Journal of Leukocyte Biology 2013, 95, 285-292, 10.1189/jlb.0313178.
  5. Francesca Finetti; Michela Pellegrini; Cristina Ulivieri; Maria Teresa Savino; Eugenio Paccagnini; Chiara Ginanneschi; Luisa Lanfrancone; Pier Giuseppe Pelicci; Cosima T. Baldari; The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity. Blood 2008, 111, 5017-5027, 10.1182/blood-2007-12-130856.
  6. Laura Patrussi; Nagaja Capitani; Enrica Cannizzaro; Francesca Finetti; Orso Maria Lucherini; Pier Giuseppe Pelicci; Cosima T. Baldari; Negative regulation of chemokine receptor signaling and B-cell chemotaxis by p66Shc. Cell Death & Disease 2014, 5, e1068-e1068, 10.1038/cddis.2014.44.
  7. Laura Patrussi; Nagaja Capitani; Francesca Cattaneo; Noemi Manganaro; Alessandra Gamberucci; Federica Frezzato; Veronica Martini; Andrea Visentin; Pier Giuseppe Pelicci; Mario M. D’Elios; et al.Livio TrentinGianpietro SemenzatoCosima T. Baldari p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from β-arrestin at early endosomes. Oncogene 2018, 37, 1534-1550, 10.1038/s41388-017-0066-2.
  8. Enrica Migliaccio; Marco Giorgio; Simonetta Mele; Giuliana Pelicci; Paolo Reboldi; Pier Paolo Pandolfi; Luisa Lanfrancone; Pier Giuseppe Pelicci; The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 1999, 402, 309-313, 10.1038/46311.
  9. M Pellegrini; F Finetti; V Petronilli; C Ulivieri; F Giusti; P Lupetti; M Giorgio; P G Pelicci; P Bernardi; C T Baldari; et al. p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis. Cell Death & Differentiation 2006, 14, 338-347, 10.1038/sj.cdd.4401997.
  10. Laura Patrussi; Nagaja Capitani; Cristina Ulivieri; Noemi Manganaro; Massimo Granai; Francesca Cattaneo; Anna Kabanova; Lucia Mundo; Stefania Gobessi; Federica Frezzato; et al.Andrea VisentinFrancesca FinettiPier Giuseppe PelicciMario Milco D’EliosLivio TrentinGianpietro SemenzatoLorenzo LeonciniDimitar G. EfremovCosima T. Baldari p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape. Haematologica 2019, 104, 2040-2052, 10.3324/haematol.2018.209981.
  11. Sonia Pacini; Michela Pellegrini; Enrica Migliaccio; Laura Patrussi; Cristina Ulivieri; Andrea Ventura; Fabio Carraro; Antonella Naldini; Luisa Lanfrancone; Piergiuseppe Pelicci; et al.Cosima T. Baldari p66SHC Promotes Apoptosis and Antagonizes Mitogenic Signaling in T Cells. Molecular and Cellular Biology 2004, 24, 1747-1757, 10.1128/mcb.24.4.1747-1757.2004.
  12. Anna Onnis; Valentina Cianfanelli; Chiara Cassioli; Dijana Samardzic; Pier Giuseppe Pelicci; Francesco Cecconi; Cosima T. Baldari; The pro-oxidant adaptor p66SHC promotes B cell mitophagy by disrupting mitochondrial integrity and recruiting LC3-II. Autophagy 2018, 14, 2117-2138, 10.1080/15548627.2018.1505153.
  13. Anna Onnis; Cosima T. Baldari; Orchestration of Immunological Synapse Assembly by Vesicular Trafficking. Frontiers in Cell and Developmental Biology 2019, 7, 1, 10.3389/fcell.2019.00110.
  14. Yan Zhao; Zhecheng Wang; Dongcheng Feng; Huanyu Zhao; Musen Lin; Yan Hu; Ning Zhang; Li Lv; Zhenming Gao; Xiaohan Zhai; et al.Xiaofeng TianJihong Yao p66Shc Contributes to Liver Fibrosis through the Regulation of Mitochondrial Reactive Oxygen Species. Theranostics 2019, 9, 1510-1522, 10.7150/thno.29620.
  15. Asad Lone; Richard A. Harris; Olivia Singh; Dean H. Betts; Robert C. Cumming; p66Shc activation promotes increased oxidative phosphorylation and renders CNS cells more vulnerable to amyloid beta toxicity. Scientific Reports 2018, 8, 1-17, 10.1038/s41598-018-35114-y.
  16. Michael Hallek; Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. American Journal of Hematology 2017, 92, 946-965, 10.1002/ajh.24826.
  17. Roberta Bichi; Susan A. Shinton; Eric S. Martin; Anatoliy Koval; George A. Calin; Rossano Cesari; Giandomenico Russo; Richard R. Hardy; Carlo M. Croce; Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proceedings of the National Academy of Sciences 2002, 99, 6955-6960, 10.1073/pnas.102181599.
  18. Graham Packham; Freda K Stevenson; Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia. Immunology 2005, 114, 441-449, 10.1111/j.1365-2567.2005.02117.x.
  19. Jan A. Burger; Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia. Hematology 2011, 2011, 96-103, 10.1182/asheducation-2011.1.96.
  20. Laura Patrussi; Nagaja Capitani; Cosima T. Baldari; Abnormalities in chemokine receptor recycling in chronic lymphocytic leukemia. Cellular and Molecular Life Sciences 2019, 76, 3249-3261, 10.1007/s00018-019-03058-9.
  21. Nagaja Capitani; Laura Patrussi; Livio Trentin; Orso Maria Lucherini; Enrica Cannizzaro; Enrica Migliaccio; Federica Frezzato; Cristina Gattazzo; Francesco Forconi; Piergiuseppe Pelicci; et al.Gianpietro SemenzatoCosima T. Baldari S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis. Blood 2012, 120, 4391-4399, 10.1182/blood-2012-04-425959.
  22. Mehrdad Matloubian; Charles G. Lo; Guy Cinamon; Matthew J. Lesneski; Ying Xu; Volker Brinkmann; Maria L. Allende; Richard L. Proia; Jason G. Cyster; Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004, 427, 355-360, 10.1038/nature02284.
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  25. Aleš Goropevšek; Marija Holcar; Tadej Avčin; The Role of STAT Signaling Pathways in the Pathogenesis of Systemic Lupus Erythematosus. Clinical Reviews in Allergy & Immunology 2016, 52, 164-181, 10.1007/s12016-016-8550-y.
  26. Francesca Cattaneo; Laura Patrussi; Nagaja Capitani; Federica Frezzato; Mario Milco D’Elios; Livio Trentin; Gianpietro Semenzato; Cosima T. Baldari; Expression of the p66Shc protein adaptor is regulated by the activator of transcription STAT4 in normal and chronic lymphocytic leukemia B cells. Oncotarget 2016, 7, 57086-57098, 10.18632/oncotarget.10977.
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Subjects: Immunology; Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Laura Patrussi
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Update Date: 12 Nov 2020
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