Differential Regulation of Mitogen-Activated Protein/ERK Kinase (MEK)1 and MEK2 and Activation by a Ras-Independent Mechanism

Self Cite

122

132

We showed previously that ERK1/2 were activated by glucose and amino acids in pancreatic ␤ cells. Here we examine and compare signaling events that are necessary for ERK1/2 activation by glucose and other stimuli in ␤ cells. We find that agents that interrupt Ca 2؉ signaling by a variety of mechanisms interfere with glucose-and glucagon-like peptide (GLP-1)-stimulated ERK1/2 activity. In particular, calmodulin antagonists, FK506, and cyclosporin, immunosuppressants that inhibit the calcium-dependent phosphatase calcineurin, suppress ERK1/2 activation by both glucose and GLP-1. Ca 2؉ signaling from intracellular stores is also essential for ERK1/2 activation, because thapsigargin blocks ERK1/2 activation by glucose or GLP-1. The glucosesensitive mechanism is distinct from that used by phorbol ester or insulin to stimulate ERK1/2 but shares common features with that used by GLP-1.

Section: Discussionsupporting

confidence: 78%

Regulation of ERK1 and ERK2 by Glucose and Peptide Hormones in Pancreatic β Cells

Arnette¹,

Gibson²,

Lawrence³

et al. 2003

Self Cite

122

132

“…We could show that this p21 cip1 induction resulted in a senescencelike phenotype. Under normal conditions it had been shown that only MEK1 is activated in response to serum stimulation (19) and that this transient activation is sufficient to provide proliferative signals but fails to induce a sustained expression of p21 cip1 and growth arrest (14). In this context we could provide evidence that MEK2 can complement for MEK1 in response to serum stimulation but causes sustained and stronger ERK activity.…”

Section: Forced Activation Of Mek2 Results In a Senescence-like Phenomentioning

confidence: 73%

“…When MEK1 activity became prominent as in the MEK2 knock down, the resulting ERK signaling provided proliferative signals. Serum stimulation indeed preferentially induces MEK1 activity in several cell types (19). Therefore, we suggest a model in which the specific activation of either MEK1 or MEK2 is part of the cellular system that enables the mitogenic switch between inhibition and enhancement of cell proliferation.…”

Section: Forced Activation Of Mek2 Results In a Senescence-like Phenomentioning

confidence: 81%

“…These differences in sequence and also prior reports suggest that MEK1 and MEK2 may not have fully overlapping functions. In several cell lines only MEK1 is activated in response to serum despite ample expression of both subtypes (19). MEK1 knock-out mice die due to placental vascularization defects, whereas MEK2 seems to be dispensable for growth and development (20,21).…”

mentioning

confidence: 99%

See 1 more Smart Citation

MEK1 and MEK2, Different Regulators of the G1/S Transition

Ussar¹,

Voss

2004

102

The ERK cascade is activated by hormones, cytokines, and growth factors that result in either proliferation or growth arrest depending on the duration and intensity of the ERK activation. Here we provide evidence that the MEK1/ERK module preferentially provides proliferative signals, whereas the MEK2/ERK module induces growth arrest at the G 1 /S boundary. Depletion of either MEK subtype by RNA interference generated a unique phenotype. The MEK1 knock down led to p21 cip1 induction and to the appearance of cells with a senescencelike phenotype. Permanent ablation of MEK1 resulted in reduced colony formation potential, indicating the importance of MEK1 for long term proliferation and survival. MEK2 deficiency, in contrast, was accompanied by a massive induction of cyclin D expression and, thus, CDK4/6 activation followed by nucleophosmin hyperphosphorylation and centrosome over-amplification. Our results suggest that the two MEK subtypes have distinct ways to contribute to a regulated ERK activity and cell cycle progression.The extracellular-regulated kinase (ERK) 1 cascade is one of three major mitogen-activated protein kinase cascades. It is predominantly involved in the control of cell proliferation, migration, cell division, and differentiation (1-3). This pathway, consisting of Raf, MEK1/2, and ERK1/2, regulates cell proliferation via its impact on cell cycle control (4). A number of observations demonstrate the importance of this cascade in the regulation of cell cycle progression. Activated variants of Raf and MEK are capable of promoting cell cycle reentry and even transformation (5-7), whereas inhibition of the ERK pathway by different means results in G 1 arrest in a variety of cell types (5,8). Activation of the ERK cascade has also been shown under certain conditions to induce cell cycle arrest (4) and even differentiation (9). Activated ERK1/2 translocates to the nucleus (10) and phosphorylates transcription factors like Ets and AP-1 family members, thereby positively regulating their activity (11). The magnitude and duration of ERK activity are, therefore, the crucial parameters determining the quality of gene expression (4).Activation of this mitogen-activated protein kinase pathway promotes the expression of cyclin D1 (12, 13) and the CDK2 inhibitory protein p21 cip1 (14). These key events result in the activation of the cyclin-dependent protein kinases CDK4/6, which promote cell cycle entry by phosphorylating the retinoblastoma tumor suppressor (Rb), leading to the release of the transcription factor E2F (15). This in turn promotes the transcription of cyclins A and E, resulting in the activation of CDK2. Activated CDK2 phosphorylates Rb at additional sites and, thus, enables DNA synthesis and centrosome duplication via further liberation of E2F (16). Furthermore, sustained expression of p21 cip1 has been shown to be responsible for the ERK-mediated proliferation inhibition (6).MEK1 and MEK2 show high homology only in their kinase domains. The N termini and the characteristic proline-rich inserts...

“…1 utilizing, as a measure of ERK1 and ERK2 activation, immunoblotting with anti-Active MAPK antisera. Labeling by this antibody has been demonstrated to closely correlate with kinase activity (34). Immunodetectable levels of active ERK1 and ERK2 reached maximum within 5 to 10 min of stimulation with IL-5.…”

Section: Time Course Of Erk1 and Erk2 Activation By Il-5-asmentioning

confidence: 92%

ERK1 and ERK2 Activation by Chemotactic Factors in Human Eosinophils Is Interleukin 5-dependent and Contributes to Leukotriene C4 Biosynthesis

Bates

Green

Bertics

2000

Eosinophils, the major immune effector cells contributing to allergic inflammation and asthma, are profoundly affected by interleukin (IL) 5 with respect to their differentiation, viability, recruitment, and cytotoxic effector functions. IL-5 enhances eosinophil responsiveness to a variety of chemotactic factors via a process called priming, although the molecular mechanism is unknown. In this study, we report that, following IL-5 priming of eosinophils, chemotactic agents including fMet-Leu-Phe, IL-8, and RANTES, promote vigorous transient activation of ERK1 and ERK2. In contrast, these chemotactic factors stimulate weak or indiscernible ERK activation in unprimed eosinophils. Furthermore, this intracellular marker of priming is selective for IL-5-related cytokines, in that it is observed following exposure to IL-5 and granulocyte macrophage-colony stimulating factor but not to interferon-␥, stem cell factor, tumor necrosis factor ␣, or IL-4. Interestingly, priming of chemoattractant-induced ERK activation is accompanied by an increase in association of tyrosinephosphorylated proteins with the adapter protein Grb2. The biological relevance of ERK activation to IL-5 priming is supported by the observation that inhibition of ERK activity by treatment with the MEK inhibitors PD98059 or U0126 inhibited the release of leukotriene C 4 stimulated by fMet-Leu-Phe in IL-5-primed eosinophils. These data provide evidence for a previously undescribed fundamental mechanism by which stimulation of IL-5 family receptors induces a rapid phenotypic alteration in the signal transduction pathways of chemotactic receptors, enabling their activation of the ERK1 and ERK2 pathway and contributing to the capacity of these cells to synthesize LTC 4 .Asthma is an inflammatory disease of the airway characterized by pronounced eosinophilia and elevated levels of IL-5.