A patient with pigmentary retinopathy, nephrotic syndrome, Ménétrier's disease, and diabetes mellitus is presented. Other complications were congestive heart failure, hypothyroidism, hypertension, ...and hypertriglyceridemia. Hypogenitalism was also suspected. Pigmentary retinopathy is known to associate with many systemic diseases, which are classified into several syndromes. This case superficially resembles Alström's disease due to the common characteristics of pigmentary retinopathy, diabetes mellitus, renal disease, and hypogenitalism. But clinically and histologically, there are distinct differences. To our knowledge, this association has never been reported. (Internal Medicine 33: 644-648, 1994)
SHPS-1 is a 120 kDa glycosylated receptor-like protein that contains immunoglobulin-like domains in its extracellular region and four potential tyrosine phosphorylation for SH2 domain binding sites ...in its cytoplasmic region. Epidermal growth factor (EGF) stimulated the rapid tyrosine phosphorylation of SHPS-1 and subsequent association of SHPS-1 with SHP-2, a protein tyrosine phosphatase containing SH2 domains, in Chinese hamster ovary cells overexpressing human EGF receptors. In the cells overexpressing SHPS-1, the tyrosine phosphorylation of SHPS-1 was more evident than that observed in parent cells. However, overexpression of SHPS-1 alone did not affect the activation of MAP kinase in response to EGF. These results suggest that SHPS-1 may be involved in the recruitment of SHP-2 from the cytosol to the plasma membrane in response to EGF.
Receptors coupled to the inhibitory G protein G<i<, such as that for lysophosphatidic acid (LPA), have been shown to activate MAP kinase through a RAS-dependent pathway. However, LPA (but not ...insulin) has now been shown to activate MAP kinase in a RAS-independent manner in CHO cells that overexpress a dominant-negative mutant of the guanine nucleotide exchange protein SOS (CHO-DeltaSOS cells). LPA also induced the activation of MAP kinase kinase (MEK), but not that of RAF1, in CHO-DeltaSOS cells. The RAS-independent activation of MAP kinase by LPA was blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) or by overexpression of a dominant-negative mutant of the gamma isoform of PI3K. Furthermore, LPA induced the activation of the atypical zeta isoform of protein kinase C (PKC-zeta) in CHO-DeltaSOS cells in a manner that was sensitive to wortmannin or to the dominant-negative mutant of PI3Kgamma, and overexpression of a dominant-negative mutant of PKC-zeta inhibited LPA-induced activation of MAP kinase. These observations indicate that G<i< protein-coupled receptors induce activation of MEK and MAP kinase through a RAS-independent pathway that involves PI3Kgamma-dependent activation of atypical PKC-zeta.
Receptors coupled to the inhibitory G protein Gi, such as that for lysophosphatidic acid (LPA), have been shown to activate MAP kinase through a RAS‐dependent pathway. However, LPA (but not insulin) ...has now been shown to activate MAP kinase in a RAS‐independent manner in CHO cells that overexpress a dominant‐negative mutant of the guanine nucleotide exchange protein SOS (CHO‐ΔSOS cells). LPA also induced the activation of MAP kinase kinase (MEK), but not that of RAF1, in CHO‐ΔSOS cells. The RAS‐independent activation of MAP kinase by LPA was blocked by inhibitors of phosphatidylinositol 3‐kinase (PI3K) or by overexpression of a dominant‐negative mutant of the γ isoform of PI3K. Furthermore, LPA induced the activation of the atypical ζ isoform of protein kinase C (PKC‐ζ) in CHO‐ΔSOS cells in a manner that was sensitive to wortmannin or to the dominant‐negative mutant of PI3Kγ, and overexpression of a dominant‐negative mutant of PKC‐ζ inhibited LPA‐induced activation of MAP kinase. These observations indicate that Gi protein‐coupled receptors induce activation of MEK and MAP kinase through a RAS‐independent pathway that involves PI3Kγ‐dependent activation of atypical PKC‐ζ.
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