The levator palpebrae superioris and orbicularis oculi are antagonistic muscles that function during movements of the eyelid. The levator also functions in conjunction with superior and inferior rectus muscles in coordinated eye/lid movements. The present study examined the innervation and morphology of these muscles in Cynomolgous monkeys (Macaca fascicularis) in order to provide a better understanding of the anatomical substrate for lid movements. Motoneurons innervating the levator and orbicularis muscles were identified and localized by retrograde transport of WGA/HRP and HRP. Retrogradely labelled levator motoneurons were distributed bilaterally throughout the caudal central division of the oculomotor nucleus. A few labelled cells were also present within the contralateral superior rectus division, possibly because of the spread of tracer at the injection site. The possibility that individual motoneurons collateralize to innervate the levator muscle bilaterally was tested by using double retrograde labelling techniques. Doubly labelled levator motoneurons could not be detected by using a combination of tracers (HRP and Fast Blue). Motoneurons innervating the upper lid portion of the orbicularis oculi muscle were distributed within the dorsal subdivision of the ipsilateral facial motor nucleus, with a few neurons in the corresponding locus of the contralateral facial nucleus. Species differences in levator motoneuron distribution, particularly distinctions in lateral-eyed versus frontal-eyed mammals, are discussed in relation to the neural control of lid movements. The levator palpebrae superioris contains three of the same ultrastructurally defined types of singly innervated muscle fiber found in the global layer of other extraocular muscles and an additional, unique slow-twitch fiber type. Moreover, the multiply innervated fiber types so characteristic of the other extraocular muscles are conspicuously absent from levator muscles. Unlike the rectus and oblique extraocular muscles, the levator lacks a layered distribution of fiber types. The morphological profiles of levator muscle fiber types are such that they generally do not respect traditional fiber classification schemes, but are consistent with a role for the levator in sustained elevation of the lid. The orbicularis oculi muscle, by contrast, exhibited three distinct fiber types that resembled categories of skeletal muscle twitch fibers. One slow-twitch and two fast-twitch fiber types were noted. On the basis of oxidative enzyme profiles and mitochondrial content, the majority of orbicularis oculi fibers would be fatigue-prone, an assessment consistent with their rapid onset/offset of acti

, MEK, but did not inhibit activation of Raf, the canonical upstream activator of MEK. These results suggest that a novel wortmanninsensitive activation pathway regulates MEK and MAP kinase in IL-2-stimulated T lymphocytes.The interaction of a resting T cell with appropriately presented antigen initiates cell cycle entry (G 0 -to G 1 -phase transition) and the expression of high-affinity interleukin-2 (IL-2) receptors (IL-2R). The binding of IL-2 to the IL-2R then elicits G 1 -to S-phase progression and commits the cell to traverse the remainder of the cell cycle. The high-affinity IL-2R is minimally composed of an IL-2R␣ (p55), IL-2R␤ (p70), and ␥ c (p64) subunit (57). However, heterodimerization of the IL-2R␤ and ␥ c intracellular domains is sufficient to trigger the mitogenic response (42,44).Although the IL-2R subunits exhibit no intrinsic protein tyrosine kinase (PTK) activity, IL-2-induced PTK activation is requisite for proliferation (47). The IL-2R␤ chain is physically and functionally coupled to the Src-family PTKs, Lck (20,21), Fyn (25,26,36), and Lyn (59). Additionally, the newly discovered JAK family PTKs, JAK1 and JAK3, are also activated by IL-2 (22, 65). Ligand-induced PTK activation elicits the downstream activation of multiple signaling components, one of which is the well-defined Ras/MAP kinase pathway. The Ras/ MAP kinase pathway comprises a set of ubiquitous and highly conserved molecules that orchestrate the delivery of signals from the cell membrane to the nucleus (reviewed in reference 34). IL-2R ligation appears to regulate Ras via the tyrosine phosphorylation of the adaptor protein, Shc (8,50,70). Tyrosine-phosphorylated Shc then associates with the Src homology 2 (SH2) domain of the adaptor protein, Grb2 (2, 70), which is constitutively bound to the mammalian homolog of the Ras guanine-nucleotide exchange protein, Son of Sevenless (SOS) (18, 31). Complex formation results in the SOS-catalyzed exchange of GDP for GTP on Ras, with the concomitant activation of Ras (17,54). Activated Ras interacts with the regulatory N terminus of the serine-threonine kinase, Raf (38,62,64,68), localizing Raf to the membrane and providing a requisite signal for Raf activation (30, 55). Activated Raf then initiates a protein kinase cascade by phosphorylating and activating MEK (33), which, in turn, phosphorylates and activates MAP kinase (14,33,43).The studies cited above define a linear signal transduction pathway leading to MAP kinase activation. However, recent data suggest that other signaling events also regulate the activity of this signaling cascade (7,28,67,69). In addition to activating the Ras pathway, IL-2 also activates phosphatidylinositol 3-kinase (PI3-K) (4, 35, 51) via a Src family kinasedependent mechanism (25). This heterodimeric lipid kinase comprises an 85-kDa regulatory subunit and a 110-kDa catalytic subunit, which phosphorylate phosphatidylinositol at the D-3 hydroxyl of the inositol ring (reviewed in reference 15). PI3-K activation correlates closely with tyrosine kinase growth facto...

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