The adaptor protein p66Shc: Comparison
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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

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.

  1. Functions of p66Shc

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

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

  1. 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

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

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.

 

  1. Conclusions and future perspectives

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

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