Caveolin-2 is a member of the caveolin gene family with no known function. Although caveolin-2 is coexpressed and heterooligomerizes with caveolin-1 in many cell types (most notably adipocytes and endothelial cells), caveolin-2 has traditionally been considered the dispensable structural partner of the widely studied caveolin-1. We now directly address the functional significance of caveolin-2 by genetically targeting the caveolin-2 locus (Cav-2) in mice. In the absence of caveolin-2 protein expression, caveolae still form and caveolin-1 maintains its localization in plasma membrane caveolae, although in certain tissues caveolin-1 is partially destabilized and shows modestly diminished protein levels. Despite an intact caveolar membrane system, the Cav-2-null lung parenchyma shows hypercellularity, with thickened alveolar septa and an increase in the number of endothelial cells. As a result of these pathological changes, these Cav-2-null mice are markedly exercise intolerant. Interestingly, these Cav-2-null phenotypes are identical to the ones we and others have recently reported for Cav-1-null mice. As caveolin-2 expression is also severely reduced in Cav-1-null mice, we conclude that caveolin-2 deficiency is the clear culprit in this lung disorder. Our analysis of several different phenotypes observed in caveolin-1-deficient mice (i.e., abnormal vascular responses and altered lipid homeostasis) reveals that Cav-2-null mice do not show any of these other phenotypes, indicating a selective role for caveolin-2 in lung function. Taken together, our data show for the first time a specific role for caveolin-2 in mammalian physiology independent of caveolin-1. Caveolae were first morphologically described in the 1950s by early electron microscopists (31, 52). These curious 50-to 100-nm membrane invaginations are most commonly found in terminally differentiated cells, such as adipocytes, endothelial cells, smooth and skeletal muscle cells, and epithelial cells. In the ensuing years, several functions were proposed for these structures, including transcytosis, potocytosis, and the concentration of certain membrane proteins.A major advance in the study of caveolae was the discovery of the 21-to 24-kDa caveolar marker protein named caveolin (now called caveolin-1) (38). Along with concomitantly developed biochemical purification techniques, caveolin-1 served as an important means to identify such compartments and to study their function. The functional role of caveolin-1 is now a primary focus of the caveolar research field.In an effort to discover other novel resident proteins of caveolae, Scherer and colleagues identified a second caveolin homologue through the microsequencing of purified adipocyte caveolar membranes. This Ϸ20-kDa protein, named caveolin-2, was Ϸ38% identical and 58% similar to caveolin-1 (44). Further study showed that in many respects caveolin-2 was tightly coregulated with caveolin-1. The two tissues with the highest caveolin-1 expression (adipose tissue and lung) are also the primary sites of caveo...

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Half of advanced human melanomas are driven by mutant BRAF and dependent on MAPK signaling. Interestingly, the results of three independent genetic screens highlight a dependency of BRAF-mutant melanoma cell lines on BRAF and ERK2, but not ERK1. ERK2 is expressed higher in melanoma compared with other cancer types and higher than ERK1 within melanoma. However, ERK1 and ERK2 are similarly required in primary human melanocytes transformed with mutant BRAF and are expressed at a similar, lower amount compared with established cancer cell lines. ERK1 can compensate for ERK2 loss as seen by expression of ERK1 rescuing the proliferation arrest mediated by ERK2 loss (both by shRNA or inhibition by an ERK inhibitor). ERK2 knockdown, as opposed to ERK1 knockdown, led to more robust suppression of MAPK signaling as seen by RNA-sequencing, qRT-PCR, and Western blot analysis. In addition, treatment with MAPK pathway inhibitors led to gene expression changes that closely resembled those seen upon knockdown of ERK2 but not ERK1. Together, these data demonstrate that ERK2 drives BRAF-mutant melanoma gene expression and proliferation as a function of its higher expression compared with ERK1. Selective inhibition of ERK2 for the treatment of melanomas may spare the toxicity associated with pan-ERK inhibition in normal tissues. Implications: BRAF-mutant melanomas overexpress and depend on ERK2 but not ERK1, suggesting that ERK2-selective inhibition may be toxicity sparing.

<p>Supplementary Figure S4 shows Western blot analysis and dose-response effects of ERK inhibition in A375 cells expressing inhibitor-resistant ERK2 with or without additional mutations affecting kinase activity or substrate docking.</p>

<p>Supplementary Figure S4 shows Western blot analysis and dose-response effects of ERK inhibition in A375 cells expressing inhibitor-resistant ERK2 with or without additional mutations affecting kinase activity or substrate docking.</p>