The delivery of soluble lysosomal proteins to the lysosomes is dependent 
primarily on the mannose 6-phosphate receptor (MPR). The MPR has been 
demonstrated to attain the early endosomes via a process that requires the 
interaction of its cytosolic domain with the GGA and AP-1 adaptor proteins. 
Additionally, the MPR can be recycled back to the trans-Golgi network (TGN) 
through its interaction with the retromer complex. Interestingly, in I-cell 
disease (ICD), in which the MPR pathway is non-functional, many soluble 
lysosomal proteins continue to traffic to the lysosomes. This observation led to 
the discovery that sortilin is responsible for the MPR-independent targeting of 
the sphingolipid activator proteins (SAPs) and acid sphingomyelinase (ASM). More 
recently, our laboratory has tested the hypothesis that sortilin is also capable 
of sorting a variety of cathepsins that exhibit varying degrees of 
MPR-independent transport. We have demonstrated that the transport of cathepsin 
D is partially dependent upon sortilin, that cathepsin H requires sortilin, and 
that cathepsins K and L attain the lysosomes in a sortilin-independent fashion. 
As a type-1 receptor, sortilin also has numerous cytosolic binding partners. It 
has been observed that like the MPR, the anterograde trafficking of sortilin and 
its cargo require both GGAs and AP-1. Similarly, the retrograde recycling 
pathway of sortilin also involves an interaction with retromer through a YXXphi 
site in the cytosolic tail of sortilin. In conclusion, the cytosolic domains of 
sortilin and MPR possess a high degree of functional homology and both receptors 
share a conserved trafficking mechanism.