Activation or suppression of NFκB by HPK1 determines sensitivity to activation-induced cell death

Brenner, Dirk; Golks, Alexander; Kiefer, Friedemann; Krammer, Peter H.; Arnold, Rüdiger

doi:10.1038/sj.emboj.7600894

Cited by 71 publications

(92 citation statements)

References 58 publications

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“…In contrast, the HPK1-C expressing cells mildly increased the sensitivity towards cell death, which was also seen previously in lymphocytes. 15 Prolonged culture of HPK1-N cells without IL-3 also significantly decreased viability (Figure 2d). This result shows that HPK1-N cells are largely apoptosisresistant, but not completely IL-3 independent, a state that would likely require additional factors.…”

Section: Resultsmentioning

confidence: 92%

“…In lymphocytes, HPK1 cleavage leads to inefficient T-cell receptor stimulation and results in apoptosis-sensitivity. 15 In myeloid progenitor cells cleaved HPK1 results in constitutive cytokineindependent signaling and enables prolonged cell survival. Similar to our finding, the potential to mediate differentiation of lymphoid and myeloid progenitors has also been shown for constitutively active b-catenin.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] While a role for HPK1 in the regulation of T-cell apoptosis was already suggested, 14 our recent studies have shown proteolytic processing of HPK1 into HPK1-C in non-apoptotic preactivated primary T cells. 15 In this study, the cleavage product HPK1-C sensitizes towards T-cell receptor-mediated cell death, while full-length HPK1 enables activation and survival of T cells. In contrast to the studies in lymphoid cells, which suggest that HPK1 acts as a life/death switch, relatively little is known about the role of HPK1 in myeloid cells.…”

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confidence: 89%

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Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation

et al. 2006

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We studied monocytic differentiation of primary mouse progenitor cells to understand molecular mechanisms of differentiation. We found a tightly controlled non-apoptotic activation of caspase-3 that correlated with differentiation. Although caspase activity was already detected during monocytic differentiation, a caspase-3 target has not been identified yet. We show that hematopoietic progenitor kinase 1 (HPK1) is processed towards its N-and C-terminal fragments during monocytic differentiation. While HPK1 is an immunoreceptor-proximal kinase in T and B cells, its role in myeloid cells is elusive. Here, we show that the N-terminal cleavage product, HPK1-N, comprising the kinase domain, confers progenitor cell survival independent of the growth factor IL-3. Furthermore, HPK1-N causes differentiation of progenitor cells towards the monocytic lineage. In contrast to full-length kinase, HPK1-N is constitutively active causing sustained JNK activation, Bad phosphorylation and survival. Blocking of caspase activity during differentiation of primary mouse progenitor cells leads to reduced HPK1-N levels, suppressed JNK activity and attenuated monocytic differentiation. Our work explains growth factor-independent survival during monocytic differentiation by caspase-mediated processing of HPK1 towards HPK1-N. Cell Death and Differentiation (2007) 14, 568-575. doi:10.1038/sj.cdd.4402042; published online 6 October 2006Within the hematopoietic system lineage commitment, differentiation and proliferation are precisely balanced throughout life, resulting in adjusted levels of myeloid and lymphoid cells. A complicated network of cytokines essentially contributes to hematopoietic homeostasis. Myeloid progenitor cells and myeloid-like cell lines respond to the cytokine interleukine-3 (IL-3) with proliferation and survival. 1 While removal of IL-3 results in cell death via apoptosis, suppression of apoptosis allows differentiation of the mouse hematopoietic progenitor cell line FDC-P1 in the absence of IL-3. 2 Monocytic differentiation of primary bone marrow and fetal liver progenitors or myeloid cell lines can be induced by IL-3 withdrawal and stimulation with monocyte-colony stimulating factor (M-CSF). 3 Monocytic differentiation is accompanied by caspase activation; 4,5 however, the molecular targets of caspase activity during monocytic differentiation have not been identified.Hematopoietic progenitor kinase 1 (HPK1) is comprised of a catalytic domain with extensive homology to the Sterile 20 kinase of the yeast Saccharomyces cerevisiae and a Cterminally located regulatory domain, called citron homology domain. 6 Ectopic expression renders full-length HPK1 active in epithelial cells resulting in selective activation of the JNK and the NFkB pathways. 7,8 Upon caspase-3 cleavage the N-terminal kinase domain of HPK1 (HPK1-N) is separated from the C-terminus (HPK1-C) resulting in suppression of NFkB. 8 In non-stimulated lymphocytes, HPK1 kinase activity is hardly detectable, but antigen receptor crosslinking leads to profound HPK1...

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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 89%

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Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation

et al. 2006

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“…[6][7][8][9] The adhesion and degranulation promoting adaptor protein (ADAP) forms a complex with Src kinase-associated phosphoprotein 55 kD (SKAP55) and Ras-associated protein 1 (Rap1)-GTP-interacting adaptor molecule (RIAM). ADAP binds to SLP-76 in a TCR-stimulation dependent manner to translocate the ADAP-SKAP55-RIAM complex to the cell membrane and further recruit the active small GTPase Rap1.…”

Section: Gck-i Kinases Regulate Nf-kb Activation Integrin Activity mentioning

confidence: 99%

Germinal center kinases in immune regulation

Yin

Shi

et al. 2012

Cell Mol Immunol

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“…Following recruitment to the TCR, HPK1 is phosphorylated on tyrosine 379 and binds the SH2 domain of SLP-76, which itself is phosphorylated by HPK1 [15][16][17][18][19]. Subsequent transphosphorylation by PKD1 and autophosphorylation within the kinase domain result in full activation of HPK1 [15], which then regulates different cellular responses including apoptosis, activationinduced cell death and autoimmunity [20][21][22].Unexpectedly, and as yet poorly understood, HPK1 negatively regulates TCR signaling [12,19,22,23]. Inhibition of NFkB through the HPK1 C-terminus in apoptotic cells and recruitment of inhibitory molecules to the HPK1 phosphorylation site on SLP-76 have been reported [14,19,22].…”

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confidence: 99%

HPK1 competes with ADAP for SLP‐76 binding and via Rap1 negatively affects T‐cell adhesion

et al. 2010

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The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFjB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1). Active Rap1, via its binding to RapL (regulator for cell adhesion and polarization enriched in lymphoid tissues), mediates LFA-1 integrin activation. We show here that HPK1, which also binds SLP-76, compete with ADAP for SLP-76 binding. In addition, HPK1 dampens Rap1 activation, resulting in decreased LFA-1 activity. Analysis of HPK1-deficient T cells revealed increased ADAP recruitment to SLP-76 and elevated Rap1 activation in those cells, leading to increased adhesion to ICAM-1 and cell spreading. Altogether, these results describe a novel function for HPK1 in linking TCR signaling to cell adhesion regulation and provide a mechanistic explanation for the negative regulatory role of HPK1 in T-cell biology.Key words: ADAP . HPK1 . LFA-1 . Rap1 . SLP-76Supporting Information available online Introduction T-cell adhesion to other immune cells or endothelium is crucial in generating an immune response. Central mediators of T-cell adhesion are integrins as, for example, the aLb2 integrin leukocyte function-associated antigen-1 (LFA-1), whose activation is mediated by chemokines or antigen receptor encounter and the b1 family of integrins (very late antigen; a4b1, a5b1 and a6b1). LFA-1 activation after TCR stimulation, also referred to as inside-out signaling, relies on a signaling module composed of the transmembranous adapter LAT (linker for activation of T cells) and the cytosolic adaptors SLP-76 (76-kDa src homology 2 domain-containing leukocyte phosphoprotein) and Gads (Grb2-related adaptor downstream of Shc) [1,2]. Two additional adapter molecules, adhesion and degranulation promoting adaptor protein (ADAP) and 55-kDa src kinase associated phosphoprotein 3220ing adapter molecule) which binds active Rap1 and thereby facilitates TCR-mediated integrin activation [5,6]. In addition, the Rap1-GTP effector regulator for cell adhesion and polarization enriched in lymphoid tissues (RapL) was recently shown to directly bind SKAP-55, which might differentially influence integrin affinity/avidity regulation [7]. Additional effectors of active Rap1 involved in integrin activation include the kinase Mst1 downstream of RapL and the serine/threonine kinase PKD1 [8][9][10].The hematopoietic progenitor kinase 1 (HPK1), a Ste20-homologous serine/threonine kinase, is activated upon TCR stimulation and feeds into MAPK and NFkB signaling [11][12][13][14]. Following recruitment to the TCR, HPK1 is pho...

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Activation or suppression of NFκB by HPK1 determines sensitivity to activation-induced cell death

Cited by 71 publications

References 58 publications

Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation

Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation

Germinal center kinases in immune regulation

HPK1 competes with ADAP for SLP‐76 binding and via Rap1 negatively affects T‐cell adhesion

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