Intracellular signalling: putting JAKs on the kinase MAP.

Tyrosine kinases of the JAK family are required for activation of both STAT transcription factors and the ERK/MAP kinase pathway, suggesting a mechanism for the optimization of gene induction via the coordinate activation of multiple transcription factors.

Social complexity and hormonal influences on sexual behavior in rhesus monkeys (Macaca mulatta).

Rhesus females in multi-animal groups mate only during the mid-follicular and periovulatory portions of their ovarian cycle, whereas females in pair-tests often mate at all cycle phases. We investigated the influence of social context on hormonal mediation of rhesus sexual behavior by observing the same males and females in both pair-tests and in single male/multi-female group-tests. Five intact adult female rhesus were tested with each of four males during their follicular, periovulatory, and luteal cycle phases as verified by steroid radioimmunoassay. Male initiated behaviors of approach, hiptouch, mount, and ejaculation were significantly above luteal levels during periovulatory group-tests, with periovulatory approach and hiptouch frequencies also significantly above follicular levels. Approach did not vary with the female's cycle phase in pair-tests and both follicular and periovulatory frequencies of hiptouch, mount, and ejaculation were higher than luteal levels. Pair-test frequencies were greater than group-test frequencies at all cycle phases, except for male approach, where the difference depended upon female cycle phase. When group-tested, females approached the male, presented, and handslapped most frequently during periovulatory tests. In pair-tests, females approached and handslapped equally during follicular and periovulatory tests and lower luteally, but presents did not vary cyclically. Females approached males significantly more frequently during pair- than group-tests, but there were no consistent differences between the two social conditions for present and handslap. In group-tests, periovulatory females were approached and threatened by other group females significantly more often that they were at other cycle phases.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone stimulates the tyrosine phosphorylation of 42- and 45-kDa ERK-related proteins.

Growth hormone (GH) influences a number of tissue-specific biological activities in diverse cell types. However, little is known about the biochemical pathway by which the signal initiated by GH binding to its cell-surface receptor is transduced. The GH receptor has been reported to be phosphorylated on tyrosine in 3T3-F442A cells, a cell line in which GH promotes differentiation and inhibits mitogen-stimulated growth; however, it is not known whether tyrosine phosphorylation plays a role in GH signal transduction. We report that GH treatment of 3T3-F442A cells resulted in the rapid tyrosine phosphorylation of at least four proteins. These included 42- (pp42) and 45-kDa (pp45) proteins immunologically related to ERK1 (extracellular signal-regulated kinase 1), a member of a family of serine/threonine protein kinases that are phosphorylated on tyrosine in response to mitogens. Prolonged phorbol ester pretreatment attenuated the tyrosine phosphorylation of pp42 and pp45 in platelet-derived growth factor-treated cells, but not in GH-treated cells. Maximal GH-stimulated tyrosine phosphorylation of pp42 and pp45 coincided with peak levels of a 42-kDa renaturable MBP kinase activity in lysates of GH-treated cells resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The observation that multiple cellular proteins are rapidly phosphorylated on tyrosine in response to physiological concentrations of GH suggests that tyrosine phosphorylation plays a role in GH signal transduction. Moreover, the stimulation of tyrosine phosphorylation of ERK-related proteins by GH suggests that mitogens and nonmitogens may employ common phosphotyrosyl proteins in the activation of ultimately distinct cellular programs.

JAK2, Ras, and Raf are required for activation of extracellular signal-regulated kinase/mitogen-activated protein kinase by growth hormone.

Protein-tyrosine kinases (PTKs) of the JAK family have been characterized on the basis of their ability to mediate the rapid induction of transcription of interferon-responsive genes through the stimulation of a class of latent cytoplasmic transcription factors known as signal transducers and activators of transcription (STATs). STAT activation, which has been described as being Ras-independent, requires tyrosine phosphorylation, but STAT transactivating activity is enhanced by phosphorylation on serine as well, probably by extracellular signal-regulated kinase/mitogen-activated protein kinase(s) (ERK/MAPK). STATs can be activated upon binding of ligands to receptor PTKs, to G-protein-linked receptors, and to cytokine receptors. Whether JAKs are required for the activation of signaling pathways other than that leading to STAT activation is not known. The binding of growth hormone (GH) to its receptor (GHR) activates JAK2 and STATs as well as ERK/MAP kinases. We have used a transient transfection system in 293 cells to evaluate the requirement for JAK2 in the activation of ERK2/MAPK by GH. We found that JAK2 is required for GH-simulated activation of ERK2/MAPK. Employing the transient expression of dominant negative forms of H-Ras and Raf-1, we determined that the GHR/JAK2-mediated activation of ERK2/MAPK is dependent on both Ras and Raf. Thus, JAK protein-tyrosine kinases may represent a common component in the activation of the ERK2/MAPK and STAT signaling pathways, which appear to bifurcate upstream of Ras activation but converge with ERK/MAPK phosphorylation of STATs.

Periovulatory changes in female sexual behavior and patterns of ovarian steroid secretion in group-living rhesus monkeys.

The behavior of nine intact group-living adult female rhesus was observed for 30 min daily with each of four adult male rhesus across a verified ovulatory menstrual cycle. Blood samples collected from females daily or on alternate days were analyzed for estradiol, testosterone, and progesterone. Female patterns of approach, follow, and initiate proximity increased several days prior to the estradiol peak, peaked on the day of the estradiol peak, then declined completely or to very low frequencies. Mounts, intromissions, and ejaculations increased significantly on the day of the estradiol peak, remained elevated for 2 more days, then declined completely by the fifth day after peak estradiol. Ejaculations never occurred outside of a 10-day period starting 4 days before the estradiol peak and ending 5 days after the estradiol peak. During this period females initiated over 90% of all approaches. Female hand slap, threaten away, and stand up increased significantly on the first day of increased copulation, remained elevated while copulation was significantly elevated, then decreased along with the decline in copulation. Ten of eleven patterns of female behavior correlated significantly with estradiol level prior to the estradiol peak. All were significantly inversely correlated with progesterone level after the estradiol peak. No pattern of female behavior correlated significantly with testosterone either before or after the estradiol peak. Similarly, male patterns of behavior correlated with female levels of estradiol and progesterone, but not testosterone. These results demonstrate a relationship between increased serum estradiol and increased female initiation of sexual behavior. The finding that some patterns of female behavior increase several days prior to copulation, whereas other behaviors increase coincident with increased copulation suggests that the behavior of group-living rhesus females serves two functions. The first is to communicate sexual interest and the second is to maintain the consort pair and increase the probability that ejaculation will occur. In addition, the strong correlation between preovulatory female behavior and estradiol level suggests that the female's behavior provides precise information about her reproductive state and could thus coordinate copulation with maximal fertility.

The result of replacement of partial or total collateral ligaments with Marlex mesh in the knees of dogs.

Marlex mesh is a synthetic material which has been used clinically to replace ligamentous structures. It serves as a scaffold for infiltration of the fibroblasts eventually becoming mature fibrocytes. In dogs, almost totally mature fibrocytes appear within the framework of the Marlex mesh prosthesis by the end of 3 months of healing.