Hedgehog Signaling Controls T Cell Killing at the Immunological Synapse

Ritter, Alex T.; Angus, Karen L.; Dinsmore, Colin J.; Earnshaw, Charles H.; Reiter, Jeremy F.; Griffiths, Gillian M.

doi:10.1126/science.1244689

Cited by 128 publications

(144 citation statements)

References 38 publications

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“…In agreement with these results, hematopoietic Ptch2 −/− did not affect B and T cell development, suggesting that the Ptch1 receptor functions as the regulator of cell-intrinsic HH ligand responses in T cell development and T cell activation (Rowbotham et al, 2009;Furmanski et al, 2012;de la Roche et al, 2013). Nevertheless, the niche Ptch2 −/− strongly enhances apoptosis rates and reduces the frequencies of all T cell subsets within the thymus, probably as a result of increased selection pressures within the thymic niche.…”

Section: Discussionsupporting

confidence: 76%

Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression

Klein¹,

Zwick²,

Kissel³

et al. 2016

J Cell Biol

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MPNs are characterized by a long indolent chronic period of disease with increased erythrocytes (polycythemia vera), increased thrombocytes (essential thrombocytosis) or cytopenias (osteomyelofibrosis), and splenomegaly, which frequently progress into a rapidly lethal leukemia. The mechanisms driving the disease acceleration finally leading to leukemic transformation are currently not understood.The hedgehog (HH) signaling pathway is involved in various aspects of embryonic development and in regeneration processes during adulthood. Canonical HH pathway activation occurs via binding of HH ligands to the PAT CHED (PTCH) receptors PTCH1/2, which results in release of the inhibited SMO OTHEN ED (SMO) receptor, followed by activation of the intracellular HH signaling complex (including SUFU) and consecutive activation of the GLI transcription factors GLI1-3. In addition, HH ligand binding to the PTCH1 receptor drives the following two SMOindependent pathways: (1) ERK phosphorylation directly mediated by the C-terminal intracellular PTCH1-signaling domain, which binds to SH3-encoding domains of proteins such as GRB2 or p85β (Chang et al., 2010) and (2) retention of activated CYC LINB1 within the cytoplasm as a result of binding to the sterol sensing domain of the PTCH receptors and therefore control of the cell cycle specifically at mitosis (Barnes et al., 2001).The exclusive activation of the SMO-dependent canonical HH signaling pathway by point mutations in PTCH1 (inactivating), SMO (activating), or SUFU (inactivating) drives cancer development of some specific tumor entities, such as medulloblastomas (Goodrich and Scott, 1998), rhabdomyosarcomas, and basal cell carcinomas (Gorlin, 1987). However, the majority of solid cancers (Thayer et al., 2003;Watkins et al., 2003;Datta and Datta, 2006) and especially hematologic malignancies, are driven by excess ligand secretion and therefore activate both the classical SMO-mediated canonical HH signaling and PTCH1-dependent noncanonical HH signaling, thereby stimulating ERK phosphorylation. In this situation, HH ligands not only act on the malignant cells but also stimulate the surrounding tumor-promoting stromal cells or niche cells, propagating part of their effects (Dierks et al., 2007;Chan et al., 2012;Lunardi et al., 2014). In chronic lym-

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Section: Discussionsupporting

confidence: 76%

Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression

Klein¹,

Zwick²,

Kissel³

et al. 2016

J Cell Biol

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“…This promotes the dissociation of SUFU-GLI complexes and the release of active full-length GLI transcription factors that translocate to the nucleus to transcribe Hedgehog target genes, bypassing the proteasome. In addition to these canonical signaling events, several groups have reported noncanonical functions for SMO, which adds further complexity to our understanding of SMO regulation [29][30][31][32][33] . Common to both canonical and noncanonical Hedgehog signaling is the modulation of SMO activity by a wide variety of small molecules.…”

Section: Role Of Smo In the Hedgehog Signaling Pathwaymentioning

confidence: 98%

Regulation of the oncoprotein Smoothened by small molecules

Sharpe

Wang²,

Hannoush³

et al. 2015

Nat Chem Biol

108

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The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway pharmacologically, many of the principles underlying the signal transduction cascade remain poorly understood. Hedgehog ligands are recognized by a unique receptor system that features the transporter-like protein Patched and the G protein-coupled receptor (GPCR)-like Smoothened (SMO). The biochemical interaction between these transmembrane proteins is the subject of intensive efforts. Recent structural and functional studies have provided great insight into the small-molecule regulation of SMO through identification of two distinct ligand-binding sites. In this Perspective, we review these recent findings and relate them to potential mechanisms for the endogenous regulation of SMO.

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“…Hh signalling is the trademark of signalling in the primary cilium, a structure absent only from haematopoietic cells and with surprising structural similarities to the synapse (Wheatley, 1995 Roche et al, 2013).…”

Section: Tcr Signallingmentioning

confidence: 99%

The cytotoxic T lymphocyte immune synapse at a glance

Dieckmann

Frazer

Asano

et al. 2016

Journal of Cell Science

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The immune synapse provides an important structure for communication with immune cells. Studies on immune synapses formed by cytotoxic T lymphocytes (CTLs) highlight the dynamic changes and specialised mechanisms required to facilitate focal signalling and polarised secretion in immune cells. In this Cell Science at a Glance article and the accompanying poster, we illustrate the different steps that reveal the specialised mechanisms used to focus secretion at the CTL immune synapse and allow CTLs to be such efficient and precise serial killers.

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Hedgehog Signaling Controls T Cell Killing at the Immunological Synapse

Cited by 128 publications

References 38 publications

Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression

Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression

Regulation of the oncoprotein Smoothened by small molecules

The cytotoxic T lymphocyte immune synapse at a glance

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