Suppressor of Cytokine Signaling 1 Regulates an Endogenous Inhibitor of a Mast Cell Protease

Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of c-Kit and interleukin-3 (IL-3) receptor signaling. We examined the role of SOCS1 in regulating IL-3-induced cell growth of primary bone marrow-derived mast cells (BMMCs) from SOCS1 –/– mice. Instead of showing increased proliferation, SOCS1-deficient BMMCs responded poorly to IL-3 and stem cell factor. SOCS1 –/– BMMCs showed increased apoptosis and defective cell cycle entry. We show that the growth retardation of SOCS1 –/– BMMCs was due to a cell intrinsic defect. Protein tyrosine phosphorylation following IL-3 stimulation was markedly diminished in SOCS1 –/– BMMCs. Intriguingly, JAK2 and STAT5 proteins were selectively diminished in SOCS1 –/– BMMCs, which also showed lower molecular mass products of p85 and Vav suggesting proteolytic degradation. Incubation of the SOCS1 –/– BMMC lysate with STAT5, p85, and Vav immunoprecipitated from SOCS1 + / + cells directly demonstrated the dysregulated proteolytic activity in SOCS1 –/– BMMCs. The proteolytic activity in SOCS1 –/– BMMCs was selectively inhibited by phenylmethylsulfonyl fluoride and soybean trypsin inhibitor, suggesting that the protease regulated by SOCS1 is a tryptase. The dysregulated tryptase in SOCS1 –/– BMMCs is unlikely to be mMCP6 or mMCP7, because the enzyme activity was not inhibited by Polybrene but was inhibited by normal mouse plasma. SOCS1 + / + BMMC lysate inhibited the proteolytic activity present in SOCS1 –/– BMMC lysate, indicating that SOCS1 –/– BMMCs lack an endogenous protease inhibitor. These results show that SOCS1 is required for the expression and/or stability of an endogenous protease inhibitor, which protects mast cells from their own proteolytic enzymes. Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of c-Kit and interleukin-3 (IL-3) receptor signaling. We examined the role of SOCS1 in regulating IL-3-induced cell growth of primary bone marrow-derived mast cells (BMMCs) from SOCS1 –/– mice. Instead of showing increased proliferation, SOCS1-deficient BMMCs responded poorly to IL-3 and stem cell factor. SOCS1 –/– BMMCs showed increased apoptosis and defective cell cycle entry. We show that the growth retardation of SOCS1 –/– BMMCs was due to a cell intrinsic defect. Protein tyrosine phosphorylation following IL-3 stimulation was markedly diminished in SOCS1 –/– BMMCs. Intriguingly, JAK2 and STAT5 proteins were selectively diminished in SOCS1 –/– BMMCs, which also showed lower molecular mass products of p85 and Vav suggesting proteolytic degradation. Incubation of the SOCS1 –/– BMMC lysate with STAT5, p85, and Vav immunoprecipitated from SOCS1 + / + cells directly demonstrated the dysregulated proteolytic activity in SOCS1 –/– BMMCs. The proteolytic activity in SOCS1 –/– BMMCs was selectively inhibited by phenylmethylsulfonyl fluoride and soybean trypsin inhibitor, suggesting that the protease regulated by SOCS1 is a tryptase. The dysregulated tryptase in SOCS1 –/– BMMCs is unlikely to be mMCP6 or mMCP7, because the enzyme activity was not inhibited by Polybrene but was inhibited by normal mouse plasma. SOCS1 + / + BMMC lysate inhibited the proteolytic activity present in SOCS1 –/– BMMC lysate, indicating that SOCS1 –/– BMMCs lack an endogenous protease inhibitor. These results show that SOCS1 is required for the expression and/or stability of an endogenous protease inhibitor, which protects mast cells from their own proteolytic enzymes. The generation, survival, proliferation, and functions of most hematopoietic cells critically depend on cytokines (1Watowich S.S. Wu H. Socolovsky M. Klingmuller U. Constantinescu S.N. Lodish H.F. Annu. Rev. Cell Dev. Biol. 1996; 12: 91-128Crossref PubMed Scopus (161) Google Scholar, 2Ward A.C. Touw I. Yoshimura A. Blood. 2000; 95: 19-29Crossref PubMed Google Scholar). A majority of the growth-promoting cytokines transduce signals by activating intracellular Janus family of protein-tyrosine kinases (JAKs) 1The abbreviations used are: JAK, Janus tyrosine kinase; BMMCs, bone marrow-derived mast cells; SCF, stem cell factor; SOCS1, suppressor of cytokine signaling 1; STAT, signal transducers and activators of transcription; E3, ubiquitin-protein isopeptide ligase; IL, interleukin; FBS, fetal bovine serum; CS, culture supernatant; CFSE, 5-(6)-carboxyfluorescein diacetate succinimidyl ester; IFN, interferon; AEBSF, 4-(2-aminoethyl)benzenesulfonylfluoride hydrochloride; PMSF, phenylmethylsulfonyl fluoride; STI, soybean tryptase inhibitor; TPCK, l-1-tosylamido-2-phenylethyl chloromethyl ketone; TLCK, 1-chloro-3-tosylamido-7-amino-2-heptanone; PBS, phosphate-buffered saline; RT, reverse transcriptase; TNF, tumor necrosis factor; PVDF, polyvinylidene difluoride; TNP, trinitrophenyl. non-covalently associated with the cytokine receptor subunits (see Refs. 3Leonard W.J. Lin J.X. J. Allergy Clin. Immunol. 2000; 105: 877-888Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar and 4O'Shea J.J. Gadina M. Schreiber R.D. Cell. 2002; 109: S121-S131Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar for reviews). The catalytic activity of JAK kinases is low in the absence of cytokine stimulation. Upon ligand binding, receptor oligomerization allows trans-autophosphorylation of the JAKs in their activation loop tyrosine, which stimulates their kinase activity. This leads to phosphorylation of the receptor chains and recruitment of adaptor proteins and second messengers to the receptor complex. The primary mediators of cytokine receptor signaling downstream of JAKs are signal transducers and activators of transcription (STATs) (5Ihle J.N. Curr. Opin. Cell Biol. 2001; 13: 211-217Crossref PubMed Scopus (593) Google Scholar), which become tyrosine-phosphorylated, dimerize, translocate into the nucleus, and induce transcription of specific sets of genes to mediate the cellular responses of cytokine stimulation. The cytokine stimulated JAK-STAT pathway is highly regulated so that the activating signals of appropriate magnitude are delivered for only the required duration (reviewed in Refs. 6Starr R. Hilton D.J. Bioessays. 1999; 21: 47-52Crossref PubMed Scopus (231) Google Scholar and 7Yasukawa H. Sasaki A. Yoshimura A. Annu. Rev. Immunol. 2000; 18: 143-164Crossref PubMed Scopus (515) Google Scholar). These signals are promptly attenuated to prevent excessive signaling and uncontrolled cellular stimulation. This is achieved by several mechanisms regulating the JAK kinase activity and the functioning of the STAT molecules. Proteintyrosine phosphatases recruited to the cytokine receptor complex dephosphorylate the JAK kinases at their activation loop tyrosine thereby attenuating their enzymatic activity. Protein inhibitor of activated STAT family proteins bind to activated STAT molecules preventing their DNA-binding activity (8Shuai K. Oncogene. 2000; 19: 2638-2644Crossref PubMed Scopus (302) Google Scholar). However, the major regulatory pathway attenuating cytokine receptor signal transduction is mediated by the SOCS family of negative feedback regulators (9Alexander W.S. Nat. Rev. Immunol. 2002; 2: 1-7Crossref Scopus (532) Google Scholar). The SOCS family contains at least eight known members. Genes encoding CIS1, SOCS1, SOCS2, and SOCS3 are rapidly induced following cytokine stimulation, and many cytokines induce the expression of several SOCS family members. All SOCS proteins have a conserved C-terminal motif called the SOCS box, which is also present in many other proteins of diverse functions (10Kile B.T. Schulman B.A. Alexander W.S. Nicola N.A. Martin H.M. Hilton D.J. Trends Biochem. Sci. 2002; 27: 235-241Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar). A central SH2 domain is also a feature of the SOCS family members, whereas the N-terminal end is quite variable in sequence and length. The regulatory function of SOCS molecules is mediated by the binding of the SH2 domain to the activation loop tyrosine of the JAK kinases (11Endo T.A. Masuhara M. Yokouchi M. Suzuki R. Sakamoto H. Mitsui K. Matsumoto A. Tanimura S. Ohtsubo M. Misawa H. Miyazaki T. Leonor N. Taniguchi T. Fujita T. Kanakura Y. Komiya S. Yoshimura A. Nature. PubMed Scopus Google Scholar, T. M. M. Matsumoto T. S. A. N. T. T. K. S. T. Nature. PubMed Scopus Google Scholar, M. M. Matsumoto T. Y. H. T. K. T. T. Sci. U. S. A. 95: PubMed Scopus Google Scholar, T.A. A. R. M. Alexander W.S. Hilton D.J. Nicola N.A. J. 1999; 18: PubMed Scopus Google Scholar, H. Misawa H. Sakamoto H. Masuhara M. Sasaki A. T. S. T. T. J.N. Yoshimura A. J. 1999; 18: PubMed Scopus Google Scholar, K. R. J. 1999; 18: PubMed Scopus Google Scholar). A of N-terminal to the SH2 domain of SOCS1 is required for the binding of the SH2 domain to the is to the binding of the SOCS1 functions a inhibitor of JAK kinase This leads to the of the JAK kinase J. J. J. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar, S. T. H. S. R. M. K. S. M. S. T. H. K. Yoshimura A. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, I. Hilton D.J. Cell. Biol. 2002; PubMed Scopus Google Scholar, R. S. J. Oncogene. 2002; 21: PubMed Scopus Google Scholar). This function of SOCS1 the SOCS box, which with of an that the JAKs and for (10Kile B.T. Schulman B.A. Alexander W.S. Nicola N.A. Martin H.M. Hilton D.J. Trends Biochem. Sci. 2002; 27: 235-241Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, M. R. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). other proteins also with SOCS1 SH2 domain and the N-terminal and of proteins are also and for K. R. J. 1999; 18: PubMed Scopus Google Scholar, S. R. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). We have that SOCS1 is rapidly induced in mast cells following stimulation with stem cell and IL-3 K. R. J. 1999; 18: PubMed Scopus Google Scholar). cells diverse in and and are the central cells in Immunol. Full Text PDF PubMed Scopus Google Scholar, J. 2001; PubMed Google Scholar). from hematopoietic stem cells into which in the to and of into or mast cells I. Curr. Opin. Google Scholar). of mast cells and their in the are critically on to SCF, IL-3 also stimulates mast cell and cells are hematopoietic cells in that be from bone or IL-3 Rev. PubMed Scopus Google Scholar). used bone marrow-derived mast cells (BMMCs) from SOCS1 –/– to SOCS1 is a regulator of IL-3 signaling. that SOCS1-deficient BMMCs showed a to IL-3 and SCF, because SOCS1 dysregulated mast cell proteolytic to of several signaling molecules. Cell from SOCS1 / were from J. The SOCS1 –/– were in from SOCS1 because SOCS1 –/– cell were from the bone of from SOCS1 –/– were All was following BMMCs were in fetal bovine and from the cell H. J. Immunol. 18: PubMed Scopus Google and from S. were used at of IL-3 and SCF, cells were at the were highly for mast of cells on not The were in culture for to and the cells were used for from and mouse and to or were from was from and p85, and were from was from Cell STAT5, and p85 were from to and were from diacetate succinimidyl was from and were from was a from R. protease inhibitor AEBSF, and were from PMSF, soybean tryptase inhibitor TPCK, TLCK, and were from inhibitor and were from inhibitor inhibitor and chloromethyl were from was from was from was from cell in and were with or for in primary were by cells were in a mast cells were with by cells cells in growth were and in binding by and Cell and Cell BMMCs were stimulated with of IL-3 or for in 1 of was the were at the of the The cells were and the was in a The for cell was used to SOCS1-deficient BMMCs BMMCs. BMMCs were with by at in for at The was with an of The cells were and stimulated with IL-3 of the in the of SOCS1-deficient or the cells were by to the of which is of cell Cell cycle was on BMMCs in growth or on cells in and 1 bovine stimulation with IL-3 for of 1 cells were and on The cells were directly in low with The cells were by and the of cells in and were of cytokine expression in mast was from 1 BMMCs in growth 1 of following the of was with and was reverse to the was on of in a The and used for of specific are and and and and and mast cell and and and and and mouse and and BMMCs were and directly in 1 1 by or in by on for of by were in to and with following the The were by from The were by in for at and for A was for other were in the protease inhibitor at cells was in 1 at 1 of was with BMMC of proteins at for 1 in a of the activity of the proteolytic or normal mouse was to a of 1 and to the BMMC lysate and for at to the end of the the of the was by in The proteins were in and by SOCS1-deficient to to IL-3 and Cell have that SOCS1 is rapidly induced in primary BMMCs following stimulation with IL-3 or SCF, and expression of SOCS1 cell with cell signals delivered the c-Kit receptor K. R. J. 1999; 18: PubMed Scopus Google Scholar). to SCF, IL-3 also stimulates mast cell and SOCS1 is a regulator of IL-3 BMMCs from SOCS1 –/– of the mast cells for showed of and on SOCS1-deficient and cells the expression of was lower in SOCS1 –/– cells cells not from cells in not SOCS1-deficient BMMCs a growth with that of BMMCs in to IL-3 or and not of the for IL-3 and c-Kit The of SOCS1-deficient BMMCs a of IL-3 or These results show that SOCS1 is for normal growth of mast cells to SOCS1-deficient Cell and the of SOCS1-deficient BMMCs to IL-3 was due to increased cell the SOCS1 –/– BMMCs with SOCS1-deficient mast cell at least cells the the increased cell in SOCS1-deficient mast cell from a cell cycle a cell cycle of cells at IL-3 stimulation and in IL-3 stimulation, the of cells in the was to in SOCS1 –/– with SOCS1-deficient BMMCs not at the These results that the of SOCS1-deficient BMMCs and their increased apoptosis from growth or from an intrinsic of cells to the cell cycle of SOCS1-deficient from a Cell –/– from signaling W.S. R. R. Nicola N.A. Hilton D.J. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, D.J. Yoshimura A. J.N. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and SOCS1-deficient are to growth by S. J. J. A. R. J. Immunol. 2002; PubMed Scopus Google Scholar). is for several cell and mast cell are to and other growth cytokines (see Immunol. Full Text PDF PubMed Scopus Google Scholar for examined the cytokine of SOCS1-deficient BMMCs by the cells showed the of the not in BMMCs or in SOCS1-deficient BMMCs which phosphorylation in not to the of SOCS1-deficient BMMCs to IL-3 or of not the growth of mast cells to IL-3 or not These results that endogenous is unlikely to be for the growth of SOCS1-deficient BMMCs. of and showed SOCS1-deficient and BMMCs not the that SOCS1-deficient BMMCs be to the growth of SOCS1-deficient BMMCs be an growth BMMCs in from SOCS1-deficient BMMCs. of BMMCs was by from SOCS1-deficient BMMCs with or IL-3 stimulation SOCS1-deficient BMMCs be on their a growth BMMCs with CFSE, a that cellular proteins and into cells cell with SOCS1-deficient BMMCs not the cell of the BMMCs These results showed that SOCS1-deficient BMMCs are not growth that on the cells and that the growth of SOCS1-deficient BMMCs is due to a cell intrinsic defect. in SOCS1-deficient signals a receptor complex of the and the Upon IL-3 binding, the JAK2 is activated and the receptor chains and several signaling STAT5 A. S. Oncogene. 2000; 19: PubMed Scopus Google Scholar). signaling are in SOCS1-deficient BMMCs, the of proteins in mast cells stimulated with of cells were directly in and with SOCS1-deficient BMMCs showed a protein-tyrosine phosphorylation following cytokine stimulation with cells with also tyrosine phosphorylation in SOCS1-deficient BMMCs in cells not the with showed of and in SOCS1-deficient BMMCs the that the of JAK2 and STAT5 were markedly lower in SOCS1-deficient BMMCs, whereas the of other proteins or were SOCS1-deficient and BMMCs the cells were by in stimulation, results that SOCS1 cytokine receptor signaling a of of signal transduction molecules. SOCS1 a of in the of signaling proteins in SOCS1-deficient BMMCs, examined other signaling molecules known to be by signaling. the proteins were immunoprecipitated cells in the of JAK2 and STAT5 in SOCS1-deficient cells was to JAK2 and STAT5, the of the p85 regulatory of and Vav were markedly diminished in SOCS1 –/– BMMCs, whereas the of the was the SOCS1 –/– and SOCS1 + / + BMMCs of the showed that the proteins not into the and from SOCS1 –/– not show a in the of STAT5 or p85, indicating that the is mast and not The that the was by on for with that the be mediated by by This was by the that p85 and Vav immunoprecipitated from SOCS1-deficient BMMCs, but not BMMCs, showed low molecular mass which of SOCS1 in Cell cells are of in which mediate the diverse functions of mast cells A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). normal mast the proteolytic activity of is regulated to prevent cellular and A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). directly SOCS1 leads to the of cellular proteins by the mast cell or by the of cellular proteins to mast cell immunoprecipitated STAT5, p85, and from BMMCs. The immunoprecipitated proteins to the were and to cell of SOCS1-deficient BMMCs. The were to the SOCS1 –/– mast cell lysate and examined for the in the of proteins on the the of immunoprecipitated STAT5 was by the SOCS1-deficient mast cell lysate in a to SOCS1-deficient mast cell lysate only a in the signal of immunoprecipitated p85 or but the lower molecular mass products in SOCS1-deficient mast cell and This was specific to a of cellular because SOCS1-deficient mast cell lysate not immunoprecipitated from cells (see These results the that SOCS1 dysregulated the mast cell proteolytic protease of SOCS1 –/– mast cells is a protease inhibitor of the dysregulated of SOCS1 –/– BMMCs. SOCS1 –/– BMMCs were in the protease and and the were for SOCS1 + / + BMMCs in the protease inhibitor were used a of the dysregulated of SOCS1 –/– BMMCs to protease SOCS1 –/– BMMCs in protease and protease were for and STAT5, p85, and proteins immunoprecipitated from SOCS1 + / + BMMCs were with SOCS1 –/– mast cell with protease in proteins that to the were and for the of the dysregulated of SOCS1 –/– BMMCs by SOCS1 –/– mast cell lysate protease inhibitor was with trypsin inhibitor to and to immunoprecipitated from SOCS1 + / + BMMCs. at that to the was by SOCS1 –/– mast cell with or were used to show of the Cell by the of SOCS1 a of SOCS1-deficient and BMMCs protease inhibitor with for and which was in the dysregulated of SOCS1-deficient BMMCs. an to an inhibitor of the dysregulated of SOCS1-deficient BMMCs and to the protease the SOCS1-deficient BMMCs in a of protease and and soybean trypsin inhibitor and to a AEBSF, the of STAT5 in SOCS1-deficient BMMCs A and not STAT5 in cells All other were in preventing STAT5 in cell and also inhibited the SOCS1-deficient mast cell lysate from STAT5 and p85 immunoprecipitated from BMMCs the dysregulated protease activity present in SOCS1-deficient mast cell lysate was by to These results demonstrated that SOCS1 dysregulated a protease in mast and inhibited the dysregulated of SOCS1-deficient BMMCs, protease inhibitor and only inhibited the the lower molecular mass of p85, and was the proteolytic These results that the dysregulated mast cell protease to or SOCS1-deficient BMMCs of dysregulated proteolytic enzymes. in SOCS1 Cell the of that the of SOCS1-deficient mast cells showed The expression of many mast cell is by and regulatory mechanisms A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). family transcription and the transcription and expression of mast cell We have the SOCS1 –/– into a and not due to a that an in the and a J. N. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). to the variable of SOCS1 –/– BMMCs be due to variable expression of a protease examined the of several other mast cell by results show that the growth of SOCS1-deficient BMMCs not with the transcription of of the genes have the protease inhibitor have that the dysregulated protease is a examined the dysregulated protease in SOCS1-deficient cells is a specific by and the of and activity is not by the protease present in mouse N. A. Matsumoto R. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). with SOCS1-deficient mast cell lysate the a that was also by trypsin but not by N. A. Matsumoto R. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). of by the dysregulated protease of SOCS1-deficient BMMCs was inhibited by with normal mouse lower These results that expression of the mast cell protease regulated by SOCS1 is is not mast cell protease regulated by SOCS1 and is inhibited by protease present in plasma. of was for 1 at with SOCS1 –/– or SOCS1 + / + BMMC lysate of or 1 of the end of the the proteins were in and with the lower or normal mouse was to the BMMC and trypsin with in SOCS1-deficient to the of an The enzymatic activity of mast cells is regulated by the by molecular A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). of in SOCS1-deficient BMMCs not from the of because of BMMCs not degradation. of mast cell in the absence of SOCS1 was due to of a or inhibitor, STAT5, p85, and Vav immunoprecipitated from BMMCs to SOCS1-deficient mast cell lysate with cell SOCS1-deficient mast cell lysate STAT5, p85, and a with lysate was to activity of the SOCS1-deficient mast cell lysate with not the proteolytic activity (see The activity was present in SOCS1 + / + and SOCS1 BMMCs but from SOCS1 –/– BMMCs, which showed of STAT5 The endogenous inhibitor present in BMMCs was by at for indicating that the inhibitor is a factor. of the IL-3 receptor the JAK-STAT pathway JAK2 and STAT5, other JAK kinases and STAT molecules have also A. S. Oncogene. 2000; 19: PubMed Scopus Google Scholar). to the of SOCS1 a negative feedback regulator of JAK SOCS1 was to uncontrolled growth of mast cells SOCS1 a role in regulating signaling and was not to growth retardation in to IL-3 or mast cell to the that mast cell proteolytic activity is dysregulated in the absence of SOCS1, and SOCS1 is a regulator of an endogenous inhibitor of a tryptase mast cell Upon activation of the by mast cells a of several Immunol. Full Text PDF PubMed Scopus Google Scholar). of the mass in a mast cell R. A. N. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the expression of is regulated at and their activity to be regulated by A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). of the by of their with the chains of are to the become activated and to the However, the activity of is from cellular by the low the of the A in the of STAT5, p85, and but not or several other proteins in SOCS1 –/– BMMCs, and a of proteolytic activity in SOCS1 –/– cells that SOCS1 the intracellular of mast cell to the of proteins that are for cell of the mast cell are at and into and A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). The of the dysregulated in SOCS1 –/– BMMCs is not are to by only protease The in activity of the dysregulated in SOCS1 –/– BMMCs was by several protease of diverse of proteolytic enzymes. the protease PMSF, trypsin inhibitor, and but not TPCK, or inhibited the proteolytic suggesting that the or dysregulated in SOCS1 –/– BMMCs are mast cells at least tryptase and J. Biol. Full Text PDF PubMed Google Scholar, N. Sci. U. S. A. PubMed Scopus Google Scholar, Y. A. Y. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). to the proteolytic activity of SOCS1 –/– mast cells by Polybrene that the dysregulated enzyme is unlikely to be J. U. M. 2000; PubMed Scopus Google Scholar). and of the or mast cell which are because of SOCS1 is by the growth of SOCS1 –/– BMMCs. to SOCS1 –/– BMMCs by M. J. A. J.N. Cell. Full Text PDF PubMed Scopus Google were because cellular activation of the JAK-STAT pathway T. N. K. J. Cell. Biol. 18: PubMed Scopus Google Scholar). the primary sequence of p85 a with at and specific for N. A. Matsumoto R. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar), the that be of the mast cell dysregulated in the absence of of the N. A. Matsumoto R. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar), that the dysregulated protease of SOCS1-deficient BMMCs in However, the protease regulated by SOCS1 is unlikely to be because a proteolytic that was not and the dysregulated protease of SOCS1-deficient BMMCs was inhibited by mouse plasma. the mast cell protease regulated by SOCS1 is or an tryptase to be most of the mast cell are in their complex the cells and have whereas is from complex and into the R. A. N. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). A majority of the are following by the cells Google by protease that of the proteins A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). of the mast cell to protease to because and are in their only is to by protease N. A. J. 1996; PubMed Scopus Google Scholar). The by which SOCS1 the mast cell to be of an endogenous mast cell protease inhibitor The in the growth and of signaling proteins in SOCS1-deficient mast cells in to the the endogenous protease of mast cells also be in mouse in activity. The tryptase inhibitor, which is present in BMMCs but in SOCS1 –/– BMMCs, is to the proteolytic directly by regulating their because of by not the proteins in SOCS1 + / + BMMCs. by regulating the expression and/or the stability of the inhibitor, SOCS1 the of mast cell by a regulatory role for SOCS1 be to for major complex expression in S. J. J. A. R. J. Immunol. 2002; PubMed Scopus Google Scholar). to the primary mediators of mast cells in and J. 2001; PubMed Google Scholar, J. M. Curr. Opin. Immunol. 2000; 12: PubMed Scopus Google Scholar, R. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The for many of the in mast cell functions are mast cell have demonstrated to mediate mechanisms A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). in are defective in the of the J. 2000; PubMed Scopus Google Scholar). The and of and a of in A. J. Clin. Immunol. 18: PubMed Scopus Google Scholar). the of stimulates from the activity of the for the of the N. A. Matsumoto R. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Immunol. 1996; Google Scholar). The mast cell mediate diverse which to in J. 2001; PubMed Scopus Google Scholar). the of mast cell proteolytic be regulated the cell in the to prevent to mast cells to many cytokines that induce SOCS1 is that SOCS1 function a in mast cells to prevent from by their own of the mast cell regulated by SOCS1 and the mechanisms the cytokine of mast cell proteolytic We J. for the of SOCS1 mice.

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