Splicing Regulators and Their Roles in Cancer Biology and Therapy

Figure 2

Cellular pathways related to SRPK1 activity. SRPK1 has been connected to important pathways of tumor biology. For instance, it can control alternative splicing events due to the activation of Receptor of Tyrosine Kinases (RTK). In this case, AKT activation can lead to SRPK1 nuclear translocation (not shown), activation of SRSF1, and generation of isoforms such as MNK2b, involved in promoting cell growth and proliferation. On the other hand, MNK2a variant expression, which is disfavored by SRSF1, can promote apoptosis. The phosphatase PHLPP is a key regulator in this process since its activity is necessary for AKT inactivation. Reduced expression of SRPK1 has been shown to decrease PHLPP recruitment to AKT leading to cellular growth increasing. Higher SRPK1 levels, however, may titrate PHLPP away from AKT complex which can also result in AKT/mTOR axis activation. Thus, either overexpression or downregulation of SRPK1 may be oncogenic, explaining why it can be found overexpressed in some tumors but also downregulated in others [106].