These functions may be Mepiroxol independent of their kinase activity. The current study supports these findings because 1) HER3 lacks high levels of kinase activity, and 2) nuclear HER3 regulation of cyclin D1 was independent of plasma membrane-bound HER3 functions and AKT signaling. Since the kinase functions of HER family members may not be solely responsible for the tumorigenic properties of these receptors, the identification of HER family TADs may serve as a map to better target nuclear HER functions in the future. Four members have ATP-independent chaperone activity but only three of them display enhanced level of expression in 3,4,5-Trimethoxyphenylacetic acid response to heat shock or stimuli that misfold and damage polypeptides. sHsps are constitutively expressed in many different tissues. In that regard, HspB1 is expressed in most tissues. HspB5 is also expressed in a wide range of tissues, including lens, heart, skeletal muscle, colon, lung and kidney whereas HspB4 is mainly expressed in the lens. These proteins have the ability to interact with each other and form hetero-oligomeric complexes. For example, in mammalian lenses, HspB4 and HspB5 form a major structural protein complex, denoted a-crystallin, involved in the refractive and light focusing properties of the lens. This complex is present in both the water soluble and insoluble fractions of the lens, especially in the nucleus region, a domain of the lens where the only other detectable sHsp, particularly in caracteous lens, is the phosphorylated form of HspB1. In addition, these Hsps share the ability to enhance the resistance of cells to the deleterious effects induced by stresses, such as those induced by heat shock, drugs, UV light and alterations in intracellular redox homeostasis. In that respect, they prevent aggregation and precipitation of misfolded or oxidized proteins. In addition, HspB1 and HspB5 can act as antioxidant proteins leading to the establishment of a pro-reducing state in cells by up-regulating the activity of antioxidant enzymes, such as glucose 6-phosphate dehydrogenase. These two chaperones also play anti-apoptotic and tumorigenic roles by interacting with specific key protein partners and are nowadays considered as potent anti-cancer therapeutic targets. Another major role of HspB1, HspB4 and HspB5 relates to their ability to modulate and stabilize cytoskeleton architecture. For instance, HspB5 chaperone activity is required to stabilize and modulate intermediate filaments assembly and avoid their aggregation. In that respect, several mutations in HspB5 have been shown to alter cytoskeletal architecture, such as the natural missense mutation R120G, which is responsible for cataracts, cardiomyopathies and desmin-related myopathies. The removal of the positive charge from arginine 120 is known to cause HspB5 partial unfolding, increased exposure of hydrophobic regions, abnormal assemblies and subunit exchange and enhanced susceptibility to proteolysis. The mutation also reduces HspB5 solubility and promotes its aggregation. In addition, it strongly impairs HspB5 chaperone activity. A fundamental property of sHsps is their ability to oligomerize. For example, HspB1 forms dynamic polydispersed structures with heterogenous native sizes comprised between 50 and 800 kDa while HspB5 native size is more uniformly distributed within the 700 to 800 kDa range. The oligomerization of HspB1 is a dynamic phenomenon linked to cell physiology that probably allows HspB1 interaction with specific client proteins. On the other hand, HspB1 large oligomers can also act as reservoirs that store stress-induced misfolded or oxidized polypeptides until they are either refolded by ATP-dependent chaperones or degraded. Another parameter to take into account is the phosphorylation of sHsps. This is a complex phenomenon because these proteins have several serine sites that can be phosphorylated different.