Signalling by the p60c-src family of protein—tyrosine kinases

Kefalas, Panagiotis; Brown, T.R.P.; Brickell, Paul M.

doi:10.1016/1357-2725(95)00024-j

Cited by 73 publications

(57 citation statements)

References 52 publications

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“…Regulation of PTHrP gene expression is, therefore, very complex, and expression is not limited to malignant tumors (10-13). Significantly, src family tyrosine kinases and rus both have been implicated in the regulation of T and B lymphocyte activation (14)(15). We speculate that in this case, PTHrP expression in lymph tissue was a nonspecific byproduct of both lymphoid hyperplasia and activation.…”

Section: Discussionmentioning

confidence: 78%

Hypercalcemia and systemic lupus erythematosus

Deftos

Burton

Baird

et al. 1996

Arthritis & Rheumatism

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Hypercalcemia is commonly caused by the increased production of parathyroid hormone-related protein (PTHrP) by a malignancy. In fact, the demonstration of increased PTHrP production in a patient with hypercalcemia is virtually pathognomonic of malignancy. We studied a patient with systemic lupus erythematosus (SLE), generalized lymphadenopathy, and hypercalcemia. Immunohistology of 2 biopsied lymph nodes revealed the abundant expression of PTHrP and the absence of malignant transformation. Although apparently rare, PTHrP production by nonmalignant lymphoid tissue may occur in SLE and should be considered in the differential diagnosis of hypercalcemia.Malignancy ranks among the leading considerations in the differential diagnosis of hypercalcemia and, overall, ranks comparably with primary hyperparathyroidism as the cause of hypercalcemia (1). Hypercalcemia as a paraneoplastic phenomenon was first described in the 1930s in patients with a variety of carcinomas and no detectable parathyroid abnormality (2). Since its discovery, parathyroid hormone-related protein (PTHrP) has been implicated in the pathogenesis of the hypercalcemia associated with a wide variety of tumors (3). In fact, hypercalcemia resulting from PTHrP secretion has been essentially pathognomonic for malignancy (3-5). Hypercalcemia appears to be rare as a primary manifestation of systemic lupus erythematosus (SLE). We report herein a patient with SLE in whom severe hypercalcemia developed in association with abundant PTHrP expression by nonmalignant lymph nodes. CASE REPORTThe patient, a 29-year-old African-American male, presented in July 1995 with hypercalcemia associated with weakness and fatigue of 3 days' duration. Two years prior to admission, he developed proteinuria of 0.9 gm/24 hours and a mild persistent elevation in the serum creatinine value of 1.5-1.9 mg/dl, with positive antinuclear antibodies (titer >1:640, speckled pattern), normal C3 and C4 levels, and negative hepatitis B surface antigen. Serum protein electrophoresis revealed polyclonal hypergammaglobulinemia.Three days before admission, he noted anorexia and fatigue. His symptoms progressed to include lightheadedness, generalized weakness, and a 10-pound weight loss. Medications at the time of admission were oral verapamil 180 mgJday and 1-2 multivitamins (containing 400 IU of vitamin D) daily. The patient had discontinued a thiazide diuretic 3 weeks prior to admission.Physical examination revealed a well-developed male with normal vital signs, except for a temperature of 99.3"F orally. Diffuse lymphadenopathy was present, involving small cervical, inguinal, and axillary nodes, which were mobile and nontender bilaterally. The spleen tip was palpable. A macular hyperpigmented rash was noted on the lower extremities.The serum calcium level on admission was 13.8 mg/dl (normal 8.4-10.2), reaching as high as 14.4 mg/dl, ionized calcium was 1.94 mg/dl (normal 1.1-1.35), and phosphorus was 4.8 mg/dl (normal 2.4-4.5). The serum PTH value was <4 pdml (normal 0-200). Serum PTHrP was und...

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Section: Discussionmentioning

confidence: 78%

Hypercalcemia and systemic lupus erythematosus

Deftos

Burton

Baird

et al. 1996

Arthritis & Rheumatism

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“…Src PTKs have conserved domains that include a myristoylated N-terminal tail, SH3 and SH2 domains, a tyrosine kinase domain, and a short C-terminal tail (15)(16)(17). The Src family is comprised of nine members, namely Src, Fyn, Yes, Yrk, Blk, Fgr, Hck, Lck, and Lyn (18). The involvement of Hck and Lyn in LPS signaling has been reported (19,20).…”

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confidence: 99%

SHP-1–Pyk2–Src Protein Complex and p38 MAPK Pathways Independently Regulate IL-10 Production in Lipopolysaccharide-Stimulated Macrophages

Okenwa

Kumar

Rego

et al. 2013

The Journal of Immunology

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The role of tyrosine phosphatase Src homology region 2 domain-containing phosphatase (SHP)-1 in LPS-activated cytokine production and inflammation was investigated by determining TNF-α and IL-10 production in splenic macrophages employing SHP-1–null (me/me) mouse model. LPS-stimulated me/me splenic macrophages secreted significantly less IL-10 with concomitantly elevated levels of TNF-α compared with wild-type (WT) macrophages irrespective of LPS dose and duration of stimulation. IL-10 significantly inhibited LPS-induced TNF-α production in both me/me and WT macrophages. The critical requirement for SHP-1 in regulating LPS-induced IL-10 and TNF-α production was confirmed by interfering with SHP-1 expression in WT macrophages and by reconstituting me/me macrophages with the SHP-1 gene. To delineate the role of SHP-1 in positive regulation of LPS-induced IL-10 production, signaling proteins representing SHP-1 targets were examined. The results reveal that tyrosine kinases Src and proline-rich tyrosine kinase 2 (Pyk2) regulate SHP-1–dependent LPS-induced IL-10 production and infer that optimal LPS-induced IL-10 production requires an assembly of a protein complex consisting of SHP-1–Pyk2–Src proteins. Moreover, LPS-induced IL-10 production also requires activation of the p38 MAPK independent of SHP-1 function. Overall, to our knowledge our results show for the first time that SHP-1 acts as a positive regulator of LPS-induced IL-10 production in splenic macrophages through two distinct and independent SHP-1–Pyk2–Src and p38 MAPK pathways.

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“…may participate in the coupling of both receptor protein tyrosine kinases and G protein-coupled receptors to ERK activation (reviewed in Refs. [47][48][49][50][51]. Indeed, a role for Fyn has been proposed in angiotensin II-induced hypertrophy of the cardiac myocyte (45 F527 the tyrosine residue at position 527 is mutated to phenylalanine rendering it insensitive to phosphorylation and inactivation by the tyrosine kinase Csk.…”

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confidence: 99%

Oncogenic src, raf, and rasStimulate a Hypertrophic Pattern of Gene Expression and Increase Cell Size in Neonatal Rat Ventricular Myocytes

Fuller

Brown²,

Sugden

1998

Journal of Biological Chemistry

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In response to hormones and growth factors, cultured neonatal ventricular myocytes increase in profile, exhibit myofibrillogenesis, and re-express genes whose expression is normally restricted to the fetal stage of ventricular development. These include atrial natriuretic factor (ANF), ␤-myosin heavy chain (␤-MHC), and skeletal muscle (SkM)-␣-actin. By using luciferase reporter plasmids, we examined whether oncogenes that activate the extracellular signal-regulated kinase cascade (src F527 , Ha-ras V12 , and v-raf) increased expression of "fetal" genes. Transfection of myocytes with src F527 stimulated expression of ANF, SkM-␣-actin, and ␤-MHC by 62-, 6.7-, and 50-fold, respectively, but did not induce DNA synthesis. Stimulation of ANF expression by src was greater than by Ha-ras V12 , which in turn was greater than by v-raf. General gene expression was also increased but to a lesser extent. The response to src F527 was inhibited by dominant-negative Ha-ras N17 . Myocyte area was increased by src F527 , Ha-ras V12 , and v-raf, and although it altered myocyte morphology by causing a pseudopodial appearance, src F527 did not detectably increase myofibrillogenesis either alone or in combination with Ha-ras V12 . A kinase-dead src mutant increased myocyte size to a much lesser extent than src F527 and also did not inhibit ANF-luciferase expression in response to phenylephrine. We conclude that members of the Src family of tyrosine kinases may be important in mediating the transcriptional changes occurring during cardiac myocyte hypertrophy and that Ras and Raf may be downstream effectors.The cardiac myocyte is a terminally differentiated cell that withdraws from cell division at around birth in mammals. In these cells, adaptive hypertrophic growth in response to an increased requirement for contractile power involves increases in cell size, protein content, and myofibrillar organization (reviewed in Ref. 1). There are also changes in gene transcription that distinguish hypertrophy from maturational growth (eutrophy). In response to hypertrophic stimuli, cultured neonatal rat ventricular myocytes initiate a rapid and transient increase in expression of immediate early genes (c-jun, c-fos, and Egr-1), followed by the re-expression of so-called "fetal" genes including atrial natriuretic factor (ANF), 1 ␤-myosin heavy chain (␤-MHC), and skeletal muscle (SkM) ␣-actin. More chronic exposure to hypertrophic agonists also elicits an increase in the expression of constitutively expressed contractile protein genes such as ventricular myosin light chain-2 and cardiac muscle ␣-actin. Many of these changes are seen during hypertrophy of the rat heart in vivo, providing a justification for the use of this model system (reviewed in Ref. 1).A wide variety of agonists induce the hypertrophic phenotype in cultured ventricular myocytes. These include agonists acting through G protein-coupled receptors such as endothelin-1 (2, 3), angiotensin II (4, 5), and ␣ 1 -adrenergic agonists (4, 6, 7). Other hypertrophic stimuli include passive ...

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Signalling by the p60c-src family of protein—tyrosine kinases

Cited by 73 publications

References 52 publications

Hypercalcemia and systemic lupus erythematosus

Hypercalcemia and systemic lupus erythematosus

SHP-1–Pyk2–Src Protein Complex and p38 MAPK Pathways Independently Regulate IL-10 Production in Lipopolysaccharide-Stimulated Macrophages

Oncogenic src, raf, and rasStimulate a Hypertrophic Pattern of Gene Expression and Increase Cell Size in Neonatal Rat Ventricular Myocytes

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