Bone morphogenetic proteins (BMPs), 1 members of the transforming growth factor-␤ superfamily, were originally identified by their novel activity to induce cartilage and bone formation in ectopic extraskeletal sites in vivo (1, 2). A number of studies have demonstrated that BMPs play essential roles in bone formation and bone cell differentiation; e.g. BMPs stimulate proteoglycan synthesis, alkaline phosphatase activity, collagen synthesis, and osteocalcin expression in chondroblasts/ osteoblasts (3-5). However, expression of BMPs (6 -8) and their receptors (9) in many tissues other than bone suggests that they are also involved in the regulation of many biological processes unrelated to bone formation. In accordance with this possibility, increasing evidence suggests a regulatory role for BMPs in early vertebrate embryogenesis such as in mesoderm induction, limb development, and hematopoietic formation (10 -14). Moreover, BMPs have drawn attention as possible regulators of central nervous system development; BMPs are expressed in multiple central nervous system regions throughout development (15)(16)(17). In this respect, we have recently demonstrated that BMP-2 acts as a neurotrophic factor; BMP-2 induces the neuronal differentiation of rat pheochromocytoma PC12 cells (18) and also promotes the survival and differentiation of striatal GABAergic neurons in culture (19).BMPs transduce their signals by binding to two different types of serine/threonine kinase receptor, type I and type II (20 -22). Upon ligand binding, type I and type II receptors form heteromeric receptor complexes. Then type I receptors are phosphorylated by type II receptors, and subsequent activation of the catalytic activity of type I receptor kinase is essential for BMP signaling. Although phosphorylation of Smad proteins by the activated type I receptor kinase was suggested to play an important role in the mediation of BMP signaling (20 -22), the precise cytoplasmic signaling pathway for BMPs through which it elicits its effects on the regulation of wide variety of biological processes remains largely unknown.We have recently shown that BMP-2 has the capacity to induce the neuronal differentiation of PC12 cells. Unlike NGF, however, BMP-2 did not induce the activation of MEK or 41-/ 43-kDa MAP kinases (ERK2 and ERK1, respectively) in these cells (18). MEK and ERK1/2 constitute a protein kinase cascade (the ERK cascade), which is one of the major cytoplasmic signaling pathways commonly activated in a wide variety of cells by diverse extracellular stimuli (23)(24)(25)(26). Activation of the cascade elicits a wide array of physiological responses such as cell division, differentiation, and secretion (23-26), and it has been reported that the activation of the cascade is necessary and sufficient for PC12 cell neuronal differentiation (27,28). However, our previous findings, which showed a clear distinction between the requirement for the activation of MEK and ERK1/2 and the ability of BMP-2 to induce PC12 cell neuronal differentiation (18), hav...

The 41-/43-kDa mitogen-activated protein (MAP) 1 kinase pathway, also called the extracellular signal-regulated kinase (ERK) pathway, is activated in a variety of cell types by diverse extracellular stimuli and is among the most thoroughly studied of signaling pathways that connect different membrane receptors to the nucleus (1, 2). Activation of the ERK pathway involves the activation of Ras at the plasma membrane, and the sequential activation of a series of protein kinases. Initially, Ras interacts with and activates Raf-1, which in turn activates MAP kinase/ERK kinase (MEK)-1 and -2 by serine phosphorylation. MEK-1/2 then catalyze the phosphorylation of 41-and 43-kDa MAP kinases (ERK2 and ERK1, respectively) on tyrosine and threonine residues, and these activated MAP kinases can phosphorylate cytoplasmic and nuclear targets. The ERK pathway participates in a wide range of cellular programs including proliferation, differentiation, and movement (1, 2).Aberrant activation of signal transducing proteins has been linked with cancer. For example, constitutively active mutants of Ras (3) and Raf-1 (4) have been observed in several human tumors, and constitutively active mutants of MEK-1 have been shown to transform mammalian cells (5, 6). We recently examined whether constitutive activation of the ERK pathway is associated with the neoplastic phenotype of human tumor cells. Constitutive activation of ERKs and MEK was observed in a relatively large number of tumors; tumor cells derived from pancreas, colon, lung, ovary, and kidney tissues showed especially high frequencies (30 -50%) and a high degree of kinase activation (7,8). Activation of the ERKs is also associated with prostate cancer progression (9). The precise cause of constitutive activation of the ERK pathway in many of these tumor cells remains unclear. However, such high frequencies of ERK/ MEK activation in human tumors indicate that specific inhibitors might be developed against these protein kinases for cancer therapy, especially for treatment of tumors showing constitutive activation of the ERK pathway.In the present study, we have examined the effect of blockade of the ERK pathway on the proliferation of human tumor cells. We utilized small molecule inhibitors of this pathway, PD98059 (10) and U0126 (11), which specifically inhibit MEK activity. Our results demonstrate that these MEK inhibitors induce a remarkable G 1 cell cycle arrest, followed by a modest apoptotic response, in tumor cells in which the ERK pathway is constitutively activated. Up-regulation of the CDK inhibitor p27Kip1 was observed in these G 1 -arrested tumor cells.

In this report, we present the terminology, definition and classification of pregnancy induced hypertension (PIH) by the Japan Society for the Study of Hypertension in Pregnancy (JSSHP). PIH is classified as gestational hypertension (GH), preeclampsia (PE), superimposed preeclampsia (S-PE) or eclampsia (E). Subclassifications by symptoms (severity and gestational age at onset) are also shown. Hypertension Research In PregnancyKey words: definition, pregnancy induced hypertension, preeclampsia TerminologyIn 2004, "Toxemia of Pregnancy" was revised to "Pregnancy induced Hypertension (PIH)" in Japan. 1,2)Definition PIH is defined as hypertension (blood pressure ≥ 140/90 mmHg) with or without proteinuria ( ≥ 300 mg/24 hours) emerging after 20 weeks gestation, but resolving up to 12 weeks postpartum.1-10) PIH is also defined as new onset proteinuria ( ≥ 300 mg/24 hours) in hypertensive women who exhibit no proteinuria before 20 weeks gestation. Classification Gestational hypertension (GH)GH is diagnosed in women whose blood pressure reaches ≥ 140/90 mmHg for the first time during pregnancy (after 20 weeks gestation), but without proteinuria. Blood pressure normalizes by 12 weeks postpartum. Preeclampsia (PE)Hypertension (blood pressure ≥ 140 / 90 mmHg) accompanied with proteinuria exceeding 300 mg/24 hours emerges for the first time after 20 weeks gestation, but both symptoms normalize by 12 weeks postpartum. Superimposed preeclampsia (S-PE)Superimposed preeclampsia is diagnosed in the following three cases. (1) New onset proteinuria ( ≥ 300 mg/24 hours) in hypertensive women who exhibit no proteinuria before 20 weeks gestation. (2) Hypertension and proteinuria documented antecedent to pregnancy and/or detected before 20 weeks gestation, one or both of which progressing after 20 weeks gestation. (3) Renal disease with proteinuria documented antecedent to pregnancy and/or detected before 20 weeks gestation, which is accompanied with new onset hypertension after 20 weeks gestation. Eclampsia (E)Eclampsia is defined as the onset of convulsions in a woman with PIH that cannot be attributed to other causes. The seizures are generalized and may appear before, during, or after labor.Subclassification by symptoms *Severity* The severity of PIH is assessed by the extent of symptoms. Both blood pressure and proteinuria are dependable indicators of severity.

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Tanimura et al. demonstrate that SH3P2 binds to and functions as a cytosolic anchor for myosin 1E (Myo1E). ERK signaling–dependent phosphorylation of SH3P2 induces the dissociation of bound Myo1E and its consequent localization to the tips of lamellipodia, where it promotes cell motility.

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