SEARCH · PubMed Health

Results for “Hippo Signaling Pathway”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed1999

Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase.

Bisphosphonates (BPs) include potent inhibitors of bone resorption used to treat osteoporosis and other bone diseases. BPs directly or indirectly induce apoptosis in osteoclasts, the bone resorbing cells, and this may play a role in inhibition of bone resorption. Little is known about downstream mediators of apoptosis in osteoclasts, which are difficult to culture. Using purified osteoclasts, we examined the effects of alendronate, risedronate, pamidronate, etidronate, and clodronate on apoptosis and signaling kinases. All BPs induce caspase-dependent formation of pyknotic nuclei and cleavage of Mammalian Sterile 20-like (Mst) kinase 1 to form the active 34-kDa species associated with apoptosis. Withdrawal of serum and of macrophage colony stimulating factor, necessary for survival of purified osteoclasts, or treatment with staurosporine also induce apoptosis and caspase cleavage of Mst1. Consistent with their inhibition of the mevalonate pathway, apoptosis and cleavage of Mst1 kinase induced by alendronate, risedronate, and lovastatin, but not clodronate, are blocked by geranylgeraniol, a precursor of geranylgeranyl diphosphate. Together these findings suggest that BPs act directly on the osteoclast to induce apoptosis and that caspase cleavage of Mst1 kinase is part of the apoptotic pathway. For alendronate and risedronate, these events seem to be downstream of inhibition of geranylgeranylation.

Alendronate↗

PubMed2000

Detection of a novel quiescence-dependent protein kinase.

We have identified a cell quiescence-specific 33-kDa cytoplasmic protein kinase (p33(QIK), Quiescence-Induced Kinase) based on induction of p33(QIK)-specific kinase activity of cells growth-arrested in the quiescent phase and deactivation upon entry into the cell cycle. Blockage of macromolecular synthesis prevents p33(QIK) from deactivation, indicating a requirement of newly synthesized regulators for deactivation of p33(QIK) during G(0)/G(1) transition. Stress shock induces additional increases of p33(QIK) activity in a quiescence-dependent manner that correlates with induction of apoptosis. Using a specific antibody to Krs1/Mst2 protein, we found that p33(QIK) is related to p63(Krs1) and is distinguishable from a 36-kDa protein kinase, which is induced through proteolytic modification of activated p63(Krs1) in proliferating cells undergoing apoptosis. p33(QIK) is constantly expressed in quiescent, proliferating, and apoptotic quiescent cells. Regulation of p33(QIK) activity involves protein phosphorylation/dephosphorylation in a proteolysis-independent manner. Regulation of p33(QIK) and related p63(Krs1) and p36 appears to involve distinct pathways in quiescent and proliferating cells, respectively. Our results illustrate the relevance of p33(QIK) activity for cell quiescence that may provide a new insight into signaling pathways regulated in cells during quiescence and quiescence-related apoptosis.

3T3 Cells↗

PubMed1999

Induction of apoptosis by SLK, a Ste20-related kinase.

We have cloned and characterized a novel murine Ste20-related kinase designated SLK. SLK displays high homology to the Ste20-related kinase LOK, and is more distantly related to MST1 and 2, both Ste20-like kinases. In addition, SLK displays high homology to microtubule and nuclear associated protein (M-NAP) and AT1-46, both of unknown function. SLK is ubiquitously expressed as multiple mRNAs in tissues and cell lines and is downregulated by mitogen depletion in differentiating myoblasts. Biochemical characterization showed that SLK overexpression activates c-Jun amino-terminal kinase 1 (JNK1). However, in vitro kinase assays indicated that SLK was not activated in response to various growth factors or stress-inducing agents. Immunofluorescence studies revealed that SLK colocalized to distinct cytosolic domains, preferentially at the periphery of the cells. In addition, prolonged overexpression of SLK in cultured fibroblasts resulted in apoptosis as demonstrated by annexin-V and TUNEL staining. Our results suggest that SLK belongs to a new family of protein kinases, mediating activation of the stress response pathway through a novel signaling cascade.

Amino Acid Sequence↗

PubMed1998

The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway.

Dorsal closure in the Drosophila embryo occurs during the later stages of embryogenesis and involves changes in cell shape leading to the juxtaposition and subsequent adherence of the lateral epidermal primordia over the amnioserosa. Dorsal closure requires the activation of a conserved c-jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) module, as it is blocked by null mutations in JNK kinase [hemipterous (hep)] and JNK [basket (bsk)]. Drosophila JNK (DJNK) functions by phosphorylating and activating DJun, which in turn induces the transcription of decapentaplegic (dpp). We provide biochemical and genetic evidence that a Ste20-related kinase, misshapen (msn), functions upstream of hep and bsk to stimulate dorsal closure in the Drosophila embryo. Mammalian (NCK-interacting kinase [NIK]) and Caenorhabditis elegans (mig-15) homologs of msn have been identified; mig-15 is necessary for several developmental processes in C. elegans. These data suggest that msn, mig-15, and NIK are components of a signaling pathway that is conserved among flies, worms, and mammals to control developmentally regulated pathways.

Amino Acid Sequence↗

PubMed2003

Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway.

Proliferation and apoptosis must be precisely regulated to form organs with appropriate cell numbers and to avoid tumour growth. Here we show that Hippo (Hpo), the Drosophila homologue of the mammalian Ste20-like kinases, MST1/2, promotes proper termination of cell proliferation and stimulates apoptosis during development. hpo mutant tissues are larger than normal because mutant cells continue to proliferate beyond normal tissue size and are resistant to apoptotic stimuli that usually eliminate extra cells. Hpo negatively regulates expression of Cyclin E to restrict cell proliferation, downregulates the Drosophila inhibitor of apoptosis protein DIAP1, and induces the proapoptotic gene head involution defective (hid) to promote apoptosis. The mutant phenotypes of hpo are similar to those of warts (wts), which encodes a serine/threonine kinase of the myotonic dystrophy protein kinase family, and salvador (sav), which encodes a WW domain protein that binds to Wts. We find that Sav binds to a regulatory domain of Hpo that is essential for its function, indicating that Hpo acts together with Sav and Wts in a signalling module that coordinately regulates cell proliferation and apoptosis.

Animals↗

PubMed1998

Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1.

Mst1 is a ubiquitously expressed serine-threonine kinase, homologous to the budding yeast Ste20, whose physiological regulation and cellular function are unknown. In this paper we show that Mst1 is specifically cleaved by a caspase 3-like activity during apoptosis induced by either cross-linking CD95/Fas or by staurosporine treatment. CD95/Fas-induced cleavage of Mst1 was blocked by the cysteine protease inhibitor ZVAD-fmk, the more selective caspase inhibitor DEVD-CHO and by the viral serpin CrmA. Caspase-mediated cleavage of Mst1 removes the C-terminal regulatory domain and correlates with an increase in Mst1 activity in vivo, consistent with caspase-mediated cleavage activating Mst1. Overexpression of either wild-type Mst1 or a truncated mutant induces morphological changes characteristic of apoptosis. Furthermore, exogenously expressed Mst1 is cleaved, indicating that Mst1 can activate caspases that result in its cleavage. Kinase-dead Mst1 did not induce morphological alterations and was not cleaved upon overexpression, indicating that Mst1 must be catalytically active in order to mediate these effects. Mst1 activates MKK6, p38 MAPK, MKK7 and SAPK in co-transfection assays, suggesting that Mst1 may activate these pathways. Our findings suggest the existence of a positive feedback loop involving Mst1, and possibly the SAPK and p38 MAPK pathways, which serves to amplify the apoptotic response.

Amino Acid Chloromethyl Ketones↗

PubMed1997

YSK1, a novel mammalian protein kinase structurally related to Ste20 and SPS1, but is not involved in the known MAPK pathways.

To clarify the upstream regulatory mechanism of mitogen-activated protein kinase (MAPK), we performed the reverse transcriptase-based polymerase chain reaction (RT-PCR) with degenerate primers synthesized based on sequences conserved among the kinase domains of yeast MAPK kinase kinases (MAPKKKs), Stell, Bck1, and Byr2. We isolated several mammalian cDNA fragments that encode kinase subdomains sharing significant sequence homology with yeast MAPKKKs. Subsequent screening of a HeLa cell cDNA library using one of these cDNA fragments as a probe resulted in the isolation of a full-length cDNA that encodes a novel protein kinase. The catalytic domain sequence of this gene product is closely related to those of budding yeast Sps1 and Ste20 protein kinases. Thus, we call this protein YSK1 (Yeast Sps1/Ste20-related Kinase 1). The transcript of YSK1 was detected in a wide range of tissues and cells. Immunoprecipitated YSK1 shows protein kinase activity. Although YSK1 is significantly similar in its kinase domain to kinases of the yeast and mammalian MAPK pathways, the overexpression of YSK1 did not lead to the activation of the ERK (extracellular signal-regulated kinase) pathway, JNK (c-Jun NH2-terminal kinase)/SAPK (stress-activated protein kinase) pathway, or p38/Mpk2 pathway. These results suggest that YSK1 may be involved in the regulation of a novel intracellular signaling pathway.

Amino Acid Sequence↗

PubMed2000

Cloning of DPK, a novel dendritic cell-derived protein kinase activating the ERK1/ERK2 and JNK/SAPK pathways.

Mitogen-activated protein kinase (MAPK) cascades are the major signaling systems transducing extracellular signals into intracellular responses, which mainly include the extracellular signal-regulated kinase (ERK) pathway, the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway, and the p38 pathway. From dendritic cell cDNA library, we isolated a full-length cDNA encoding a potentially novel 898-residue kinase, which was designated DPK. The protein contained a potential kinase domain at the N-terminal exhibiting homology with MEKK1-, MEKK2-, MEKK3-, MEKK4-, MEKK5-, Tpl-2-, and p21-activated kinases (PAKs), but no GTPase-binding domain which is characteristic of PAKs. Northern blotting analysis showed that DPK was ubiquitously expressed in normal tissues, with abundant expression in kidney, skeletal muscle, heart, and liver. When overexpressed in transfected NIH3T3 cells, it could activate both the ERK1/ERK2 pathway and the SAPK pathway in a dose-dependent manner, but not affect the p38 pathway. These findings suggested that DPK might be a novel candidate MAPKKK.

Amino Acid Sequence↗

PubMed2002

Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation.

MST1 is a member of the Sterile-20 family of cytoskeletal, stress, and apoptotic kinases. MST1 is activated by phosphorylation at previously unidentified sites. This study examines the role of phosphorylation at several sites and effects on kinase activation. We define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. Phosphorylation of MST1 in subdomain VIII was catalyzed by active MST1 via intermolecular autophosphorylation, enhanced by homodimerization. Active MST1 (wild-type or T183E), but not inactive Thr(183)/Thr(187) mutants, was also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues. Cells expressing active MST1 were mostly detached, whereas with inactive MST1, adhesion was normal. Active MKK4, JNK, caspase-3, and caspase-9 were detected in the detached cells. These cells also contained all autophosphorylated and essentially all caspase-cleaved MST1. Similar phenotypes were elicited by a caspase-insensitive D326N mutant, suggesting that kinase activity, but not cleavage of MST1, is required. Interestingly, an S327E mutant mimicking Ser(327) autophosphorylation was also caspase-insensitive, but only when expressed in caspase-3-deficient cells. Together, these data suggest a model whereby MST1 activation is induced by existing, active MST kinase, which phosphorylates Thr(183) and possibly Thr(187). Dimerization promotes greater phosphorylation. This leads to induction of the JNK signaling pathway, caspase activation, and apoptosis. Further activation of MST1 by caspase cleavage is best promoted by caspase-3, although this appears to be unnecessary for signaling and morphological responses.

3T3 Cells↗

PubMed1994

Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center.

B lymphocytes which reside in the germinal center region of lymphoid follicles are functionally and phenotypically distinct from the surrounding mantle zone B cells. We have isolated cDNA clones for several genes that are differentially expressed between these two populations of B lymphocytes. One such gene, BL44, is preferentially expressed in germinal center B cells. The nucleotide sequence of a 2,874-base pair BL44 cDNA was determined and a 2,451-bp open reading frame found that encodes for a 97-kDa serine/threonine protein kinase referred to as GC kinase. It has an NH2-terminal catalytic domain most similar to that of the Drosophila NinaC protein and the yeast STE20 protein. GC kinase mRNA transcripts are not unique to germinal center B cells and are found in several other tissues, including brain, lung, and placenta. The GC kinase protein was immunoprecipitated from transfected COS cells and from the Burkitt cell line RAMOS. GC kinase immunoprecipitated from transfected COS cells phosphorylated the substrates casein and myelin basic protein. In addition, a 97-kDa phosphoprotein likely to be GC kinase itself was detected. GC kinase may participate in an important signal transduction pathway in germinal center B cells.

3T3 Cells↗

PubMed2000

Caspase 3 cleavage of the Ste20-related kinase SLK releases and activates an apoptosis-inducing kinase domain and an actin-disassembling region.

We have demonstrated that a novel Ste20-related kinase, designated SLK, mediates apoptosis and actin stress fiber dissolution through distinct domains generated by caspase 3 cleavage. Overexpression of SLK in C2C12 myoblasts stimulated the disassembly of actin stress fibers and focal adhesions and induced apoptosis, as determined by annexin V binding and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling analysis. SLK was cleaved by caspase 3 in vitro and in vivo during c-Myc-, tumor necrosis factor alpha, and UV-induced apoptosis. Furthermore, cleavage of SLK released two domains with distinct activities: an activated N-terminal kinase domain that promoted apoptosis and cytoskeletal rearrangements and a C-terminus domain that disassembled actin stress fibers. Moreover, our analysis has identified a novel conserved region (termed the AT1-46 homology domain) that efficiently promotes stress fiber disassembly. Finally, transient transfection of SLK also activated the c-Jun N-terminal kinase signaling pathway. Our results suggest that caspase-activated SLK represents a novel effector of cytoskeletal remodeling and apoptosis.

Actins↗

PubMed2000

Molecular cloning and characterization of a novel human STE20-like kinase, hSLK.

We have cloned a human counterpart to a guinea pig STE20-like kinase cDNA, designated human SLK (hSLK), from a human lung carcinomatous cell line A549 cDNA library. hSLK cDNA encodes a novel 1204 amino acid serine/threonine kinase for which the kinase domain located at the N-terminus shares considerable homology to that of the STE20-like kinase family. The C-terminal domain of hSLK includes both the coiled-coil structure and four Pro/Glu/Ser/Thr-rich (PEST) sequences, but not the GTPase-binding domain (GBD) that is characteristic of the p21-activated kinase (PAK) family, polyproline consensus binding sites, or the Leu-rich domain seen in the group I germinal center kinases (GCKs). Northern blot analysis indicated that hSLK was ubiquitously expressed. hSLK overexpressed in COS-7 cells phosphorylates itself as well as myelin basic protein used as a substrate. On the other hand, hSLK cannot activate any of the three well-characterized mitogen-activated protein kinase MAPK (ERK, JNK/SAPK and p38) pathways. Moreover, hSLK kinase activity is not upregulated by constitutive active forms of GTPases (RasV12, RacV12 and Cdc42V12). These structural and functional properties indicate that hSLK should be considered to be a new member of group II GCKs.

Amino Acid Sequence↗

PubMed1999

The Drosophila STE20-like kinase misshapen is required downstream of the Frizzled receptor in planar polarity signaling.

The Drosophila misshapen (msn) gene is a member of the STE20 kinase family. We show that msn acts in the Frizzled (Fz) mediated epithelial planar polarity (EPP) signaling pathway in eyes and wings. Both msn loss- and gain-of-function result in defective ommatidial polarity and wing hair formation. Genetic and biochemical analyses indicate that msn acts downstream of fz and dishevelled (dsh) in the planar polarity pathway, and thus implicates an STE20-like kinase in Fz/Dsh-mediated signaling. This demonstrates that seven-pass transmembrane receptors can signal via members of the STE20 kinase family in higher eukaryotes. We also show that Msn acts in EPP signaling through the JNK (Jun-N-terminal kinase) module as it does in dorsal closure. Although at the level of Fz/Dsh there is no apparent redundancy in this pathway, the downstream effector JNK/MAPK (mitogen-activated protein kinase) module is redundant in planar polarity generation. To address the nature of this redundancy, we provide evidence for an involvement of the related MAP kinases of the p38 subfamily in planar polarity signaling downstream of Msn.

Actins↗

PubMed2005

WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1.

The WNK1 and WNK4 genes have been found to be mutated in some patients with hyperkalemia and hypertension caused by pseudohypoaldosteronism type II. The clue to the pathophysiology of pseudohypoaldosteronism type II was its striking therapeutic response to thiazide diuretics, which are known to block the sodium chloride cotransporter (NCC). Although this suggests a role for WNK1 in hypertension, the precise molecular mechanisms are largely unknown. Here we have shown that WNK1 phosphorylates and regulates the STE20-related kinases, Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). WNK1 was observed to phosphorylate the evolutionary conserved serine residue located outside the kinase domains of SPAK and OSR1, and mutation of the OSR1 serine residue caused enhanced OSR1 kinase activity. In addition, hypotonic stress was shown to activate SPAK and OSR1 and induce phosphorylation of the conserved OSR1 serine residue, suggesting that WNK1 may be an activator of the SPAK and OSR1 kinases. Moreover, SPAK and OSR1 were found to directly phosphorylate the N-terminal regulatory regions of cation-chloride-coupled cotransporters including NKCC1, NKCC2, and NCC. Phosphorylation of NCC was induced by hypotonic stress in cells. These results suggested that WNK1 and SPAK/OSR1 mediate the hypotonic stress signaling pathway to the transporters and may provide insights into the mechanisms by which WNK1 regulates ion balance.

Amino Acid Motifs↗

PubMed2004

Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1.

The ablation of the protein kinase Raf-1 renders cells hypersensitive to apoptosis despite normal regulation of extracellular signal-regulated kinases, which suggests that apoptosis protection is mediated by a distinct pathway. We used proteomic analysis of Raf-1 signaling complexes to show that Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (MST2). Raf-1 prevents dimerization and phosphorylation of the activation loop of MST2 independently of its protein kinase activity. Depletion of MST2 from Raf-1-/- mouse or human cells abrogated sensitivity to apoptosis, whereas overexpression of MST2 induced apoptosis. Conversely, depletion of Raf-1 from Raf-1+/+ mouse or human cells led to MST2 activation and apoptosis. The concomitant depletion of both Raf-1 and MST2 prevented apoptosis.

Animals↗

PubMed1999

A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinase Misshapen and activates Jun kinase.

Two families of protein kinases that are closely related to Ste20 in their kinase domain have been identified - the p21-activated protein kinase (Pak) and SPS1 families [1-3]. In contrast to Pak family members, SPS1 family members do not bind and are not activated by GTP-bound p21Rac and Cdc42. We recently placed a member of the SPS1 family, called Misshapen (Msn), genetically upstream of the c-Jun amino-terminal (JNK) mitogen-activated protein (MAP) kinase module in Drosophila [4]. The failure to activate JNK in Drosophila leads to embryonic lethality due to the failure of these embryos to stimulate dorsal closure [5-8]. Msn probably functions as a MAP kinase kinase kinase kinase in Drosophila, activating the JNK pathway via an, as yet, undefined MAP kinase kinase kinase. We have identified a Drosophila TNF-receptor-associated factor, DTRAF1, by screening for Msn-interacting proteins using the yeast two-hybrid system. In contrast to the mammalian TRAFs that have been shown to activate JNK, DTRAF1 lacks an amino-terminal 'Ring-finger' domain, and overexpression of a truncated DTRAF1, consisting of only its TRAF domain, activates JNK. We also identified another DTRAF, DTRAF2, that contains an amino-terminal Ring-finger domain. Msn specifically binds the TRAF domain of DTRAF1 but not that of DTRAF2. In Drosophila, DTRAF1 is thus a good candidate for an upstream molecule that regulates the JNK pathway by interacting with, and activating, Msn. Consistent with this idea, expression of a dominant-negative Msn mutant protein blocks the activation of JNK by DTRAF1. Furthermore, coexpression of Msn with DTRAF1 leads to the synergistic activation of JNK. We have extended some of these observations to the mammalian homolog of Msn, Nck-interacting kinase (NIK), suggesting that TRAFs also play a critical role in regulating Ste20 kinases in mammals.

Amino Acid Sequence↗

PubMed2003

M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase.

Multinucleated bone-resorbing osteoclasts (Ocl) are cells of hematopoietic origin that play a major role in osteoporosis pathophysiology. Ocl survival and activity require M-CSF and RANK ligand (RANKL). M-CSF signals to Akt, while RANKL, like TNFalpha, activates NF-kappaB. We show here that although these are separate pathways in the Ocl, signaling of all three cytokines converges on mammalian target of rapamycin (mTOR) as part of their antiapoptotic action. Accordingly, rapamycin blocks M-CSF- and RANKL-dependent Ocl survival inducing apoptosis, and suppresses in vitro bone resorption proportional to the reduction in Ocl number. The cytokine signaling intermediates for mTOR/ribosomal protein S6 kinase (S6K) activation include phosphatidylinositol-3 kinase, Akt, Erks and geranylgeranylated proteins. Inhibitors of these intermediates suppress cytokine activation of S6K and induce Ocl apoptosis. mTOR regulates protein translation acting via S6K, 4E-BP1 and S6. We find that inhibition of translation by other mechanisms also induces Ocl apoptosis, demonstrating that Ocl survival is highly sensitive to continuous de novo protein synthesis. This study thus identifies mTOR/S6K as an essential signaling pathway engaged in the stimulation of cell survival in osteoclasts.

Acid Phosphatase↗

PubMed1999

Human JIK, a novel member of the STE20 kinase family that inhibits JNK and is negatively regulated by epidermal growth factor.

Mammalian members related to Saccharomyces cerevisiae serine/threonine kinase STE20 can be divided into two subfamilies based on their structure and function. The PAK subfamily is characterized by an N-terminal p21-binding domain (also known as CRIB domain), a C-terminal kinase domain, and is regulated by the small GTP-binding proteins Rac1 and Cdc42Hs. The second group is represented by the GCK-like members, which contain an N-terminal catalytic domain and lack the p21-binding domain. Some of them have been demonstrated to induce c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) cascade, while others have been shown to be activated by a subset of stress conditions or apoptotic agents, although little is known about their specific function. Here, we have identified a novel human STE20-related serine/threonine kinase, belonging to the GCK-like subfamily. This kinase does not induce the JNK/SAPK pathway, but, instead, inhibits the basal activity of JNK/SAPK, and diminishes its activation in response to human epidermal growth factor (EGF). Therefore, we designated this molecule JIK for JNK/SAPK-inhibitory kinase. The inhibition of JNK/SAPK signaling pathway by JIK was found to occur between the EGF receptor and the small GTP-binding proteins Rac1 and Cdc42Hs. In contrast, JIK does not activate nor does it inhibit ERK2, ERK6, p38, or ERK5. Furthermore, JIK kinase activity is not modulated by any exogenous stimuli, but, interestingly, it is dramatically decreased upon EGF receptor activation. Thus, JIK might represent the first member of the STE20 kinase family whose activity can be negatively regulated by tyrosine kinase receptors, and whose downstream targets inhibit, rather than enhance, JNK/SAPK activation.

3T3 Cells↗